Molecular Targeted Therapy For Anticancer Treatment

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Molecular targeted therapy for anticancer treatment

1✉
Hye-Young Min1 and Ho-Young Lee
© The Author(s) 2022
Since the initial clinical approval in the late 1990s and remarkable anticancer effects for certain types of cancer, molecular targeted
therapy utilizing small molecule agents or therapeutic monoclonal antibodies acting as signal transduction inhibitors has served as
a fundamental backbone in precision medicine for cancer treatment. These approaches are now used clinically as first-line therapy
for various types of human cancers. Compared to conventional chemotherapy, targeted therapeutic agents have efficient
anticancer effects with fewer side effects. However, the emergence of drug resistance is a major drawback of molecular targeted
therapy, and several strategies have been attempted to improve therapeutic efficacy by overcoming such resistance. Herein, we
summarize current knowledge regarding several targeted therapeutic agents, including classification, a brief biology of target
kinases, mechanisms of action, examples of clinically used targeted therapy, and perspectives for future development.
Experimental & Molecular Medicine (2022) 54:1670–1694; https://doi.org/10.1038/s12276-022-00864-3

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INTRODUCTION and aromatase inhibitors, which have been used for treatment of
Cancer is one of the main causes of disease-related death hormone receptor (HR)-dependent breast cancer and male and
worldwide. According to Global Cancer Observatory (GLOBOCAN) female reproductive cancers11; immune checkpoint inhibitors
estimates of cancer incidence and mortality, there were approxi- [e.g., antibodies against programmed cell death protein 1 (PD-1),
mately 19.3 million new cancer cases and almost 10.0 million programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-
cancer deaths in 2020 globally1. The cancer-related burden (such associated protein 4 (CTLA-4)], which activate host antitumor
as incidence and mortality) is expected to be 28.4 million cases in immunity in a direct or indirect manner8,12; and even targeted
2040, which is a 47% increase compared with that in 2020, largely cytotoxic therapy that interferes with a specific cellular target
due to increases in risk factors, such as aging, socioeconomic (e.g., methotrexate, a dihydrofolate reductase inhibitor)10. Despite
development, overweight status, and smoking1,2. Therefore, it is the anticancer effectiveness of these targeted therapies, these
necessary to develop efficacious treatment strategies for patients drugs are only applicable for patients harboring targetable driver
with cancer. mutations or aberrations13,14. In addition, side effects or toxicity
Several therapeutic modalities, such as surgery, radiation caused by unexpected cross-reactivity with normal cells and
therapy, and systemic anticancer therapy, have been applied emergence of intrinsic or acquired drug resistance hamper their
clinically for cancer treatment, either alone, in combination, or effectiveness13,14. Notwithstanding some limitations, targeted
sequentially, depending on the stage, resectability, biology, therapy has resulted in remarkable survival benefits in some
comorbidities, and patient’s overall functional performance3,4. types of cancer and has led to a revolution in the fundamental
Systemic anticancer therapy, involving a wide range of anticancer concept of cancer treatment, providing the fundamental back-
drugs for treatment, palliation, symptom alleviation, and quality bone for evolution toward precision or personalized medicine in
of life improvement, includes cytotoxic chemotherapy, hormonal cancer13,15. Herein, we summarize current knowledge with
agents, targeted therapy, and antitumor immunotherapy5,6. respect to molecular targeted therapy, including the history,
Cytotoxic chemotherapy inhibits the survival of actively prolifer- types, and mechanism of action, and provide examples of
ating cells by disrupting the synthesis of DNA and RNA, blocking clinically available targeted therapy. In this paper, ‘targeted
mitosis, and/or forming covalent bonds with DNA, RNA, and therapy’ is confined to conventional molecular targeted therapy
proteins7, and it has been extensively used in adjuvant or (signal transduction inhibitors).
neoadjuvant therapy as well as in palliative therapy7. Due to the
disadvantages of chemotherapy, including side effects and Brief history of molecular targeted therapy
toxicity associated with nonselective action against actively Paul Ehrlich first proposed the concept of targeted therapy in the
proliferating normal cells2,8, there has been innovative develop- 1890s as a “magic bullet” that would be completely specific for the
ment of ‘targeted’ cancer treatment with increased cancer cell target and thus safe without any additional toxicity14,16. This
specificity8. Targeted therapy may include the following: conven- theory was initially applied to infectious diseases but not to
tional molecular targeted agents, such as small molecule anticancer therapy due to insufficient knowledge of the etiology
inhibitors or antibodies that specifically inhibit signal transduction and biology of cancer14,16; however, this concept has since been
pathways involved in growth, proliferation, and survival9,10; expanded to cancer treatment14,16. Trastuzumab, an anti-HER2
hormonal agents such as estrogen receptor (ER) antagonists monoclonal antibody, and imatinib, a small molecule tyrosine
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Republic of Korea. ✉email: [email protected]
1
Received: 10 March 2022 Revised: 18 July 2022 Accepted: 25 July 2022

Published online: 12 October 2022
H.-Y. Min and H.-Y. Lee
1671
Fig. 1 Timeline for the approval of selected molecular targeted therapeutic agents. The first FDA-approved targeted therapeutic agent for
each cellular target (denoted in blankets) is indicated in the timeline.
kinase inhibitor targeting the BCR-ABL fusion-mediated aberrantly Mechanisms of the anticancer effects of molecular targeted
activated ABL kinase, were developed and clinically approved in therapy. Molecular targeted therapies achieve anticancer effects
1998 and 2001 for treatment of HER2-positive breast cancer and through various mechanisms, such as inhibition of cell prolifera-
Philadelphia chromosome-positive chronic myelogenous leuke- tion, metastasis, and angiogenesis, induction of apoptosis, and
mia, respectively14,17–19. The success of imatinib in the clinic has reversal of multidrug resistance2 (Fig. 2a). Several molecular
served as the paradigm for extensive use of small molecule kinase targeted therapeutic agents also facilitate host antitumor immu-
inhibitors as anticancer therapy8,17, and a number of anticancer nity by potentiating CD8+ T-cell recruitment and natural killer cell
molecular targeted therapies have been approved for clinical use cytotoxicity, downregulating immunosuppressive myeloid cells,
in cancer patients8,17. The timeline for the development of the and inducing immunogenic cell death, either alone or in
main molecular targeted therapy is illustrated in Fig. 1. combination with chemotherapeutic agents29. Therapeutic mAbs
create a bridge between tumor cells and immune cells via Fab
Types, mechanisms of action and resistance, and adverse region-mediated binding to a target protein of tumor cells and
effects/toxicity of molecular targeted therapy recognition of immune cells through the Fc region of antibodies30,
To date, numerous molecular targeted therapeutic agents have resulting in opsonization and antibody-dependent cellular cyto-
been used clinically for cancer treatment. The classification of toxicity (ADCC) toward tumor cells30 (Fig. 2b). A recent study
molecular targeted therapeutic agents and their targets, mechan- demonstrated that neutrophils mediate trogoptosis (Fig. 2c), the
ism of action, side effects, and toxicity are described below. phenomenon of transferring surface molecules of interacting cells
onto immune cells31,32, which causes lytic/necrotic death of
Types of molecular targeted therapy. The two major types of antibody-opsonized cancer cells33. mAbs and SMIs also exert
molecular targeted therapy are monoclonal antibodies (mAbs) immune cell-induced cytotoxic effects on cancer cells by
and small molecule kinase inhibitors (SMKIs)8,14. mAbs target activating complement and complement-dependent cytotoxi-
extracellular ligands (e.g., bevacizumab targets vascular endothe- city30,34, facilitating antigen processing by increasing expression
lial growth factor [VEGF]), membrane receptors (e.g., trastuzumab of major histocompatibility complex molecules30,35,36 and regulat-
targets HER2 and cetuximab; panitumumab targets EGFR), and ing cytokine/chemokine expression30,37.
membrane-bound proteins (e.g., rituximab targets CD20), acting
through ligand-binding blockade, ligand‒receptor interaction Mechanisms underlying resistance to molecular targeted therapy.
neutralization, or target molecule internalization/degradation14,20. The emergence of drug resistance is a major hurdle of efficacious
Except for inhibitors targeting nonkinase cellular proteins (e.g., anticancer treatment. Primary (intrinsic) resistance is defined as a
mutated KRAS and proteasome) or epigenetic modulators (e.g., refractory status to initial therapy due to intrinsic cellular, genetic,
histone deacetylases), most SMKIs suppress protein kinases and/or epigenetic alterations. Hyperactivation of compensatory
involved in the transformation, growth, proliferation, and survival signaling pathways [e.g., truncated HER2 expression (p95HER2) for
of cancer cells. As deregulation of protein kinases (e.g., activation resistance to anti-HER2 mAbs38; KRAS mutation or MET amplifica-
by gain-of-function genetic mutation, gene amplification, auton- tion for resistance to anti-EGFR therapy38,39], mutations in kinase
omous activation, and chromosomal rearrangement) has been domains (e.g., EGFR exon 20 insertion for resistance to anti-EGFR
associated with cancer development and progression21–24, protein therapy38), isoform switching (e.g., BRAF/CRAF switching for
kinases have been regarded as important targets for developing resistance to anti-BRAF therapy40), and metabolic reprogram-
molecular targeted therapies. Protein kinases are classified into ming40 during disease development are involved in primary
receptor tyrosine kinases, nonreceptor (cytoplasmic) tyrosine resistance to molecular targeted therapy.
kinases, serine/threonine kinases, and lipid kinases based on their Human cancers often exhibit substantial intratumor hetero-
subcellular localization, substrate type, and hallmark roles in geneity, which is a main driver for emerging acquired therapy
cancer21 (Fig. 2). A detailed explanation of the signal transduction resistance as a result of expansion of rare preexisting refractory
by receptor tyrosine kinase is described in previous studies24,25. populations during treatment in initial responders39,41,42. Various
SMKIs block the enzymatic activity of the aforementioned molecular and cellular alterations [e.g., development of second-
kinases via several modes of action26. Type I kinase inhibitors bind ary mutations [EGFR T790M and C797S38,43,44, BCR-ABL T315I44,
to the ATP-binding pocket of the active conformation of the BRAF V600E40,44, Bruton’s tyrosine kinase (BTK) C418S44, ana-
enzyme [DFG (Asp-Phe-Gly)-in and αC-helix-in]26, whereas type I1/2 plastic lymphoma kinase (ALK) G1202R, and ROS1 G2032R and
or type II inhibitors bind the enzyme in an inactive conformation D2033N44], alterations in noncoding RNAs44, activation of
(type I1/2: DFG-Asp in; type II: DFG-Asp out)21,26. Type III and type IV bypassing signaling pathways, including MET, HER2, type I
inhibitors allosterically suppress kinase activity by binding either insulin-like growth factor receptor (IGF-1R), and AXL43,45,
to a site next to the ATP-binding pocket or one remote from the mutations in BRAF, PTEN, PIK3CA, and MAP2K143,45, interaction
ATP-binding pocket located in the kinase substrate-binding with stromal cells in the tumor microenvironment43,46, altera-
site21,26,27. Type V inhibitors act as bivalent inhibitors binding to tions in E3 ubiquitin ligases47, reactivation of developmental
two different portions of the kinase lobe21,26. Type VI inhibitors processes, such as the epithelial-mesenchymal transition (EMT),
covalently bind an enzyme to inhibit kinase activity26,28. A recent acquisition of cancer stem cell (CSC)-associated phenotypes, and
paper describes the detailed mode of action of each type of kinase transdifferentiation to small-cell lung cancer43,48] have also been
inhibitor26, and some examples are listed in Table 1. shown to induce acquired therapy resistance. The mechanisms
Experimental & Molecular Medicine (2022) 54:1670 – 1694

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Fig. 2 Mechanism of the anticancer effect of molecular targeted therapy. a Schematic diagrams of the main protumor signal transduction
pathways and their inhibition by molecular targeted therapeutic agents. b, c Schematic diagrams for antibody-dependent cellular cytotoxicity
b and trogoptosis c. See the text and relevant references for details.
Table 1. Classes of selected kinase inhibitors26,28.

Class Mechanism of action Examples
Type I Binding in the ATP-binding pocket of the active conformation of the cabozantinib, ceritinib, gefitinib, palbociclib,
enzyme (DFG-in and αC-helix-in) pazopanib, ponatinib, ruxolitinib, tofacitinib
Type I1/2 Binding in the ATP-binding pocket of the inactive conformation of the dasatinib, imatinib, lapatinib, lenvatinib, nilotinib,
Type II enzyme (type I1/2: DFG-Asp in; type II: DFG-Asp out) regorafenib, sorafenib, sunitinib, vemurafenib
Type III Allosteric inhibitors binding to a site in the kinase domain either next to trametinib, everolimus, sirolimus, temsirolimus
Type IV the ATP-binding pocket or remote from the ATP-binding pocket
Type V Bivalent inhibitors that bind two different portions of the kinase lobe lenvatinib28
Type VI Covalent inhibitors afatinib, ibrutinib
26
In Ref. , lenvatinib is classified as a type I1/2 inhibitor.
of resistance to each molecular targeted therapy are summarized have indicated that cancer patients who receive targeted therapy
in Tables 2–6. may experience various side effects and toxicity. The side effects
of targeted therapy include asthenia, anorexia, dyspnea, diarrhea,
Adverse effects and toxicity of molecular targeted therapy. Despite nausea, vomiting, mucositis, skin rash, fever, hand-foot syn-
improved specificity for cancer cells, epidemiological studies drome, fatigue, cardiotoxicity, hypertension, and bleeding49,50.

Table 2. Receptor tyrosine kinase inhibitors that have been clinically used for cancer treatment.
Target Generic name Brand name First approved Additional indication Drug resistance Side effects/toxicity References
(Code name) (Company) indication (Year) mechanism (selected) (selected)
8,52,63,195–197
EGFR1 Gefitinib Iressa Advanced NSCLC2 after failure Metastatic NSCLC EGFR T790M mutation Skin rash, nausea,
(ZD1839) (AstraZeneca) of both platinum-based and harboring EGFR mutations MET amplification diarrhea, transaminitis,
docetaxel (first-line therapy, 2015) HER2 amplification ILD3-like disorders,
chemotherapies (2003) Small-cell lung cancer hematuria
transformation
8,50,52,64,195–197
EGFR Erlotinib Tarceva Locally advanced or metastatic Metastatic NSCLC EGFR T790M mutation Skin rash, diarrhea,
(OSI-744) (Roche/Astellas) NSCLC after failure of prior harboring EGFR mutations HGF overexpression ocular toxicity
chemotherapy regimen (2004) (first-line therapy, 2013) MET amplification
HER2 amplification
Small-cell lung
cancertransformation
196,198,199
EGFR Afatinib Gilotrif Metastatic NSCLC with kinase Advanced squamous cell EGFR T790M mutation Skin rash, diarrhea
(BIBW2992) (Boehringer activating mutations (2013) carcinoma of the lung MET amplification
Ingelheim) after treatment with EGFR V843I mutation
platinum-based
chemotherapy (2016)
67,200,201
EGFR Dacomitinib Vizimpro Metastatic NSCLC with kinase EGFR T790M/C797S Skin toxicity, dermatitis

(PF-00299804) (Pfizer) activating mutations (2018) mutation acneiform, paronychia,
diarrhea
8,79,195,202–204
EGFR Osimertinib Targrisso 1st- or 2nd-generation EGFR- Advanced NSCLC with Loss of EGFR T790M Skin rash, diarrhea,
(AZD9291) (AstraZeneca) TKI-refractory NSCLC (2015) mutated EGFR, regardless mutation mucositis/stomatitis,
of T90M mutation (2018) EGFR C797S mutation paronychia,
MET amplification pneumonitis, cardiac
Wild-type EGFR failure
amplification
72
EGFR Lazertinib4 Leclaza Advanced or metastatic Loss of EGFR T790M Skin rash, itchiness,
(YH25448) (Yuhan/Janssen) NSCLC (2021) mutation paresthesia, muscle
EGFR activating spasm, headache,
mutation/amplification diarrhea, anorexia
EGFR C797S mutation
87–89,205–208
EGFR Cetuximab Erbitux Metastatic CRC5 (2004) Head and neck squamous RAS/BRAF mutation Infusion reactions,
(ImClone) cell carcinoma (2006) EGFR S492R mutation acneform skin rash, nail
MET amplification disorder
PTEN loss
88,89,206,208
EGFR Panitumumab Vectibix Metastatic CRC (2006) RAS/BRAF mutation Integument toxicity,
(Abgenix/Amgen) MET amplification skin toxicity, diarrhea
PTEN loss
79,80
EGFR Amivantamab Rybrevant Advanced NSCLC with EGFR Infusion reactions
(JNJ-61186372) (Janssen Biotech) exon 20 insertion mutations ocular toxicity,
progressing after platinum- peripheral edema,
based chemotherapy (2021) hypoalbuminemia
79,81
EGFR Mobocertinib Exkivity Advanced NSCLC with EGFR Diarrhea, skin toxicity
(TAK-788) (Takeda exon 20 insertion mutations
Pharmaceuticals) progressing after platinum-
based chemotherapy (2021)
8,56,90,209
HER2 Trastuzumab Herceptin Metastatic breast Locally advanced Truncation of HER2 Cardiotoxicity
(Genentech/ cancer (1998) unresectable or metastatic extracellular domain
Roche) HER2+ gastric or (p95 HER2)
gastroesophageal junction PTEN loss
(GEJ) adenocarcinoma in IGF-1R expression
combination with PIK3CA mutation
pembrolizumab (2021)
1673
1674
Table 2. continued
8,90,210
HER2 Pertuzumab Perjeta HER2+ early breast cancer Diarrhea, nausea,
(Genentech/ (EBC) with high risk of alopecia, fatigue,
Roche) recurrence (2017) peripheral neuropathy,
vomiting
91
HER2 Zanidatamab (Zymeworks) Advanced/metastatic HER2- Diarrhea, infusion-
(ZW25) expressing biliary tract cancers related reactions
82,83,209,211
HER2 Lapatinib Tykerb HER2+ metastatic breast Triple-positive metastatic Crosstalk with ER Diarrhea, skin rash,
(GW-572016) (GlaxoSmithKline/ cancer progressing with prior breast cancer (in HER2 mutation asymptomatic
Novartis) therapy (in combination with combination with PIK3CA mutation cardiotoxicity
capecitabine, 2007) letrozole, 2010) AXL elevation
HER2 L755S mutation
56,84,209,211,212
HER2 Neratinib Nerlynx Extended adjuvant therapy for Advanced or metastatic TORC1 hyperactivation Diarrhea
(HKI-272) (Puma HER2+ breast cancer (2017) HER2+ breast cancer RAS upregulation
Biotechnology) progressing with prior
therapy (in combination
with capecitabine, 2020)
85,211
HER2 Tucatinib Tukysa Advanced or metastatic HER2+ HER2 L755S mutation Diarrhea
(ONT-380) (Seattle Genetics) breast cancer (in combination cardiotoxicity
with trastuzumab and
capecitabine, 2020)
79,96,98,99,213
ALK Crizotinib Xalkori Locally advanced or metastatic ROS1-positive ALK mutation (G1269A, Nausea, vomiting,
ROS1 (PF-02341066) (Pfizer) ALK+ NSCLC (2011) NSCLC (2016) C1156Y, E1210K, diarrhea, visual
MET I1171T, S1206C/Y, disturbance, sinus
I1151T/N/S, 1174 C/L/V, bradycardia, liver

V1180L, L1196M) enzyme abnormalities
95,96,213
ALK Ceritinib Zykadia ALK+ metastatic NSCLC after ALK+ metastatic NSCLC ALK mutation (G1202R, Diarrhea, nausea,
(LDK378) (Novartis) failure of crizotinib (first-line therapy, 2017) F1174C/L/V, 1151Tins, vomiting, fatigue,
therapy (2014) L1152P, C1156Y) elevated level of
transaminase
79,96,213
ALK Alectinib Alecensa ALK-rearranged advanced/ ALK+metastatic NSCLC ALK mutation (G1202R, Photosensitivity,
(CH5424802) (Chugai recurrent NSCLC with (first-line therapy, 2017) V1180L and I1171T/N/ dysgeusia, myalgia,
Pharmaceutical/ crizotinib resistance (2015) S) upregulated creatinine
Roche MET amplification phosphokinase
79,101,102,213
ALK Brigatinib Alunbrig ALK-rearranged metastatic ALK double mutation Pneumonitis, nausea,
EGFR (AP26113) (ARIAD NSCLC (2017) (G1202R, E1210K and diarrhea, fatigue
Pharmaceuticals) S1206C or D1203N)
8,92,203
ALK Lorlatinib Lorbrena ALK-rearranged metastatic ALK+ metastatic Compound ALK Edema, .
ROS1 (PF-6463922) (Pfizer) NSCLC (2018) NSCLC (2021) mutation including cholesterolemia,
(second/third-line treatment, (regular approval) G1202R, I1171N/T/S, peripheral neuropathy,
accelerated approval) and L1198F hypertriglyceridemia,
ALK L1256F mutation CNS effects
MET amplification
79,99,214
MET Capmatinib Tabrecta Metastatic NSCLC harboring MET mutation at D1228 Nausea, diarrhea,
(INC280) (Novartis) MET exon 14 skipping (2020) and Y1230 (D1228 A/E/ peripheral edema,
G/H/N/V/Y, Y1230 C/D/ hypoalbuminemia,
H/N/S) increased blood
creatinine
79,99,214
MET Tepotinib Tepmetko Metastatic NSCLC harboring MET mutation at D1228 Nausea, vomiting,
(EMD 1214063) (Merck) MET exon 14 skipping (2021) and Y1230 (D1228 A/E/ peripheral edema,
G/H/N/V/Y, Y1230 C/D/ hypoalbuminemia,
H/N/S) increased blood
creatinine

Table 2. continued
106,107
TRK Larotrectinib Vitrakvi Locally advanced or metastatic TRKA F589L/G595R/ Upregulation of serum
(LOXO-101) (Loxo Oncology/ solid tumors with NTRK gene G667C, TRKC G623R/ AST/ALT, dizziness,
Bayer) fusion (2018) G696A mutation fatigue, nausea,
constipation
106,107
TRK Entrectinib Rozlytrek Solid tumors with NTRK gene TRKA G595R/G667C, Fatigue, dysgeusia,
ALK (RXDX-101) (Genentech) fusion and NSCLC harboring TRKC G623R mutation nausea, vomiting,
ROS1 ROS1 rearrangement (2019) paresthesia, myalgia,
diarrhea
109,215–217
FLT3 Midostaurin Rydapt AML6 harboring FLT3 FLT3 N676K, F691L Nausea, febrile
c-Kit (PKC412, (Novartis) mutations (2017) mutation neutropenia, mucositis,
PDGFR CGP 41251) FLT3 ligand vomiting, headache,
Src overexpression petechiae, fever
VEGFR RAS/MAPK mutation
JAK, PI3K/Akt
activation
109,215–217
FLT3 Gilteritinib Xospata FLT3-mutated refractory FLT3 F691L mutation upregulation of hepatic
AXL (ASP2215) (Astellas Pharma) AML (2018) RAS/MAPK mutation transaminase/creatine

JAK, PI3K/Akt phosphokinase, edema,
activation cytopenia, febrile
neutropenia
109,215–217
VEGFRs Sorafenib Nexavar Advanced RCC7 (2005) HCC8 (2008) FLT3 F691L, Y842C/H, Hand-foot syndrome,
PDGFR-β (BAY 43-9006) (Bayer/Onyx Locally recurrent or D835F/V/Y mutation asthenia,
c-Kit Pharmaceuticals) metastatic, progressive FLT3 ligand gastrointestinal
FLT3 DTC9 refractory to overexpression irritation, cytopenia,
RET radioactive iodine JAK, PI3K/Akt infection, diarrhea,
RAFs treatment (2013) activation cardiovascular toxicity,
fatigue
8,126,218,219
PDGFR-α/β Sunitinib Sutent Advanced RCC (2006) Pancreatic neuroendocrine Angiogenic factor Mucositis, diarrhea, skin
VEGFR1/2/3 (SU11248) (Pfizer) Imatinib-resistant tumor (2011) upregulation abnormality, taste
CSF-1R GIST10 (2006) Autophagy alteration
c-Kit, RET Metabolic adaptation
FLT3 Stromal cell
recruitment
220
VEGFR1/2/3 Pazopanib Votrient Advanced/metastatic Advanced soft-tissue Angiogenic factor Hepatic injury, fatigue,
PDGFR-α/β (GW786034) (GlaxoSmithKline/ RCC (2009) sarcoma previously upregulation hand-food syndrome,
FGFR1 Novartis) treated with Stromal cell myelosuppression

FGFR3 chemotherapy (2012) recruitment
c-Kit
220
VEGFR1/2/3 Lenvatinib Lenvima Progressive radioactive iodine- Advanced RCC (recurrent Angiogenic factor Hypertension, diarrhea,
PDGFR-α (E7080) (Eisai/Merck) refractory thyroid or metastatic) (2016) upregulation fatigue/asthenia
FGFRs cancer (2015) Unresectable HCC (2018) Stromal cell
c-Kit Advanced RCC in recruitment
RET combination with
pembrolizumab (2021)
220
MET Cabozantinib Cometriq Cometriq: medullary thyroid Cabometyx: HCC (second- Angiogenic factor Diarrhea, palmar-
VEGFR2 (XL184) (capsule) cancer (2012) line, 2019) upregulation plantar
c-Kit Cabometyx Cabometyx: RCC (2016) Stromal cell erythrodysesthesia
RET (tablet) recruitment syndrome
AXL (Exelixis)
Tie2
FLT3
220
VEGFRs Axitinib Inlyta Advanced or metastatic Angiogenic factor Hypertension, diarrhea,
(AG 013736) (Pfizer) RCC (2012) upregulation fatigue
Stromal cell
recruitment
1675
1676
Table 2. continued
221
VEGFR2 Vandetanib Zactima Medullary thyroid RET V804M/L mutation Diarrhea, skin rash,
EGFR3 ZD6474) aprelsa cancer (2011) Activation of RAS/ RAF/ folliculitis, nausea,
GFR AstraZeneca) MEK pathway fatigue, hypertension,
ET QT interval
prolongation
220,222
VEGFR1/2/3 Regorafenib Stivarga Metastatic CRC (2012) Advanced GIST (2013) KIT V654A, D816V Hypertension, hand-
Tie2 BAY 73-4506) (Bayer) Advanced HCC (2018) mutation food skin reaction,
PDGFR-α/β diarrhea, fatigue
FGFR1/2
c-Kit
RET
RAFs
223
VEGFR1/2/3 Tivozanib Fotivda Relapsed or refractory Infiltration of Hypertension,
PDGFR-β (AV-951, KRN- (AVEO RCC (2021) myeloid cells hoarseness, fatigue,
c-Kit 951) Pharmaceuticals headache,
/Kyowa Kirin) diarrhea, rash
222
PDGFR-α Avapritinib Ayvakit Unresectable or metastatic Memory impairment,
c-Kit (BLU-285) (Blueprint GIST harboring PDGFRA exon cognitive disorder,
Medicines) 18 mutations, including intracranial bleeding
D842V (2020)
222
PDGFR-α Ripretinib Qinlock Advanced GIST treated with Alopecia
c-Kit (DCC-2618) (Deciphera three or more kinase
Pharmaceuticals) inhibitors, including
imatinib (2020)
91,224,225
FGFR Erdafitinib Balversa Metastatic urothelial Metastatic or locally FGFR1 V561M/F Hyperphosphatemia,
(JNJ‑42756493) (Janssen cancer (2018) advanced bladder cancer mutation dry mouth, diarrhea,
Pharmaceuticals) with an FGFR3 or FGFR2 FGFR2 N549H fatigue, stomatitis
alteration (2019) mutation
p.E565A and p.L617M
single-nucleotide
variants
91,224–226
FGFRs Pemigatinib Pemazyre Previously treated, FGFR1 V561M/F Hyperphosphatemia,
(INCB054828) (Incyte unresectable, locally mutation dry mouth, diarrhea,
Corporation) advanced, or metastatic FGFR2 N549H fatigue, stomatitis
cholangiocarcinoma with mutation
FGFR2 fusion or other
rearrangements (2020)
91,224,225
FGFRs Futibatinib (Taiho Locally advanced/metastatic p.E565A and p.L617M Hyperphosphatemia,
(TAS-120) Pharmaceutical) cholangiocarcinoma with single-nucleotide dry mouth, diarrhea,
FGFR2 gene variants paronychia,
rearrangement (2021) FGFR2 V564F mutation
91,224,225
FGFRs Infigratinib Truseltriq Locally advanced/metastatic FGFR2 N549H, N550H/ Hyperphosphatemia,
(BGJ398) (QED cholangiocarcinoma with K, V564F, E565A, dry mouth, diarrhea,
Therapeutics FGFR2 gene K660M, L618V, K641R fatigue, stomatitis
/Helsinn) rearrangement (2021) mutation
91,224,225
FGFRs Derazantinib (Basilea Intrahepatic Hyperphosphatemia,
(ARQ 087) Pharmaceutica cholangiocarcinoma (2021) dry mouth, diarrhea,
/Merck) fatigue, stomatitis

1677
Specifically, acneiform rash, a skin rash with an acne-like
appearance, is a common side effect of anti-EGFR therapy50,51,
References
and hypertension is a common side effect of bevacizumab and

anti-VEGF receptor (VEGFR) therapy52. These common side
227,228
227,228
effects are related to therapy response52. Severe toxicities, such
as colitis, digestive perforation, toxic cardiomyopathy, pneumo-
nitis/interstitial lung disease, acute respiratory distress syndrome,
anemia, hypertension posterior reversible encephalopathy syndrome, necrotizing
fasciitis, acute renal failure, and hypersensitivity, have been
Side effects/toxicity
AST/ALT elevation,
AST/ALT elevation,
observed in patients receiving molecular targeted therapy, such

as antiangiogenic agents, anti-EGFR therapy, and anti-HER2
hypertension
therapy53. The side effects and toxicity of each molecular

(selected)
targeted therapy are summarized in Tables 2–6.
SMKIs and mAbs in targeted cancer therapy

By focusing on U.S. Food and Drug Administration (FDA)-approved
kinase inhibitors, target kinases and examples of clinically used
mechanism (selected)
inhibitors are briefly introduced below.

Drug resistance
RET mutation at
RET mutation at
Receptor tyrosine kinase inhibitors

Inhibitors targeting the EGFR family: The human EGFR family
G810, Y806
G810, L730
comprises four members of the ErbB lineage of proteins (ErbB1/

EGFR, ErbB2/HER2, ErbB3/HER3, and ErbB4/HER4)8,54,55. Except
for HER2, due to its inability to bind ligand54, EGFR family
members form homo- and heterodimers and are activated via
binding of ligands, such as EGF, epiregulin, transforming growth
factor-α (TGF-α), and neuregulins8,54,55. Approximately 25% of all
types of breast cancer patients show HER2 gene amplification or
Additional indication
overexpression56. EGFR kinase-activating mutations [e.g., exon 19

microdeletions and L858R point mutations in the cytoplasmic
tyrosine kinase domain, truncation of extracellular domain
(EGFRvIII)] as well as overexpression without genetic alterations
may occur in solid tumors57–59. These genetic changes cause
abnormal EGFR activation in a ligand-independent fashion60.
Exon 19 microdeletions and L858R point mutations are
commonly found in patients with non-small cell lung cancer
(NSCLC), particularly in nonsmoking east Asian females59,61, and
EGFRvIII is frequently observed in glioblastoma57–59. Additional
Metastatic RET fusion-positive
Metastatic RET fusion-positive
EGFR mutations, including E884K, D761Y, T854A, and exon 20

thyroid cancer with RET
Advanced or metastatic
insertion, have been detected in NSCLC and found to confer

EGFR TKI resistance62.
Several EGFR TKIs have been developed over the past decades
alterations (2020)
indication (Year)
First approved
and are clinically used for treatment of patients with NSCLC

NSCLC (2020)
NSCLC (2020)
harboring kinase-activating mutations (Table 2). Gefitinib and

erlotinib are first-generation EGFR-TKIs8,63,64 that interact with the
ATP-binding pocket of EGFR in either the active or inactive
conformation26. Second-generation EGFR TKIs, such as afatinib
and dacomitinib, are irreversible EGFR inhibitors that covalently
bind to the ATP-binding pocket of EGFR8,65,66. Despite the great
efficacy of first- and second-generation EGFR-TKIs in patients with
kinase-activating mutations in EGFR64,67, the EGFR T790M muta-
(Eli Lilly/Loxo
Brand name
tion in exon 2068 is associated with acquired resistance to these

(Company)
Medicines)
Oncology)
(Blueprint
Retevmo
first- and second-generation EGFR-TKIs67,69 (e.g., approximately

Gavreto
half of NSCLC patients acquire resistance to first-generation EGFR-

EGFR: epidermal growth factor receptor.
TKIs69). EGFR T790M provides advantages for the growth and

DTC: differentiated thyroid carcinoma.
survival of cancer cells69 and limits the therapeutic efficacy of

GIST: gastrointestinal stromal tumor.
NSCLC: non-small cell lung cancer.
EGFR TKIs through both steric hindrance and potentiated ATP

Approved in Republic of Korea.
Generic name
HCC: hepatocellular carcinoma.
binding62,69. Accordingly, EGFR TKIs targeting the T790M mutation

(Code name)
AML: acute myeloid leukemia.

Selpercatinib
(LOXO-292)
ILD: interstitial lung disease.

Pralsetinib
have been developed and clinically utilized. Osimertinib, a third-

(BLU-667)
RCC: renal cell carcinoma.
generation EGFR TKI, inhibits EGFR kinase activity by forming a

CRC: colorectal cancer.
covalent bond with the cysteine-797 residue in the ATP-binding

continued
pocket and shows an approximately 200 times greater inhibitory

effect on mutant EGFR [L858R or exon 19 deletion mutations
additionally harboring T790M (L858R/T790M or exon19del/
T790M)] than on wild-type EGFR70,71. Another third-generation
Table 2.
Target
EGFR TKI, lazertinib, is an orally available, CNS-penetrable, and

RET
RET
irreversible EGFR TKI that inhibits EGFR T790M and kinase-

10
activating mutations72. Despite the approval of these agents for

1
2
3
4
5
6
7
8
9

1678
clinical use, clinical trials evaluating recently developed EGFR TKIs, system (CNS)95,96,100, additional ALK inhibitors have been devel-
including canertinib (CI-1033, a pan-ErbB inhibitor), naquotinib oped. The second-generation ATP-competitive ALK/ROS1 inhibitor
(ASP8273, third-generation EGFR TKI), and rociletinib (CO-1686, ceritinib and the ATP-competitive ALK inhibitor alectinib have
third-generation EGFR TKI), have been discontinued owing to been approved for treatment of patients with crizotinib resis-
safety and risk/benefit issues73. Nonetheless, EGFR cysteine-797 tance96. In contrast to crizotinib and ceritinib, alectinib can
mutation was found in 14% of NSCLC patients with acquired penetrate the CNS, curing NSCLC patients with brain metastasis
osimertinib resistance, leading to the development of fourth- and preventing progression of CNS metastasis8,96. Additional
generation EGFR TKIs74,75. Several fourth-generation EGFR TKIs blood‒brain barrier (BBB)-permeable ATP-competitive ALK TKIs
(e.g., BLU-945, EAI045, and OBX02-011) that target EGFR T790M have been developed, including brigatinib, which is effective
and EGFR C797S have been evaluated in preclinical and clinical against FMS-like tyrosine kinase 3 (FLT3), insulin-like growth factor
settings74,76–78. Additionally, two inhibitors targeting EGFR exon receptor (IGF-1R), EGFR, and several ALK mutations associated
20 insertions, such as amivantamab and mobocertinib, have been with resistance to crizotinib, ceritinib, and alectinib101,102, and
recently approved for the treatment of patients with advanced lorlatinib, with inhibitory effects against all recognized ALK
NSCLC with progression after platinum-based chemotherapy79–81 mutations except the L1198F mutation8,92.
(Table 2). SMKIs approved to date for clinical use in patients with
HER2-positive breast cancer include lapatinib, neratinib, and MET inhibitors: MET is an RTK activated by hepatocyte growth
tucatinib8,56,82. Lapatinib is an orally available TKI that reversibly factor (HGF) and mediates several physiological processes, such
interacts with the ATP-binding site of EGFR and HER283, and as embryogenesis and tissue repair; aberrant activation of MET
neratinib is an orally available agent that covalently binds to the by genetic alterations plays an important role in the prolifera-
ATP-binding site of the tyrosine kinase domain of EGFR and HER2, tion, invasion, and metastasis of tumor cells103. Alterations in the
resulting in irreversible EGFR/HER2 inhibition84. Tucatinib is an MET gene, such as amplification, mutation, and alternative
orally available, selective, and reversible HER2 inhibitor that splicing (MET exon 14 skipping), have been detected in NSCLC
competitively interacts with the ATP-binding site of HER285. and other solid tumors8,99. MET overexpression is associated
Several clinical trials for recently developed HER2-targeting TKIs with poor prognosis and resistance to chemotherapeutic agents,
are also ongoing86. including EGFR targeted therapy8,104. In addition, MET gene
In addition to SMKIs, mAbs targeting EGFR and HER2 have been exon 14 skipping leads to constitutive activation of the MET
used in the clinic (Table 2). EGFR mAbs, including cetuximab and signaling pathway and confers sensitivity to MET inhibitors105.
panitumumab, have been clinically used for treatment of patients MET inhibitors, such as orally available ATP-competitive small-
with metastatic colorectal cancer87–89. HER2-targeting mAbs, such molecule TKIs and monoclonal antibodies, have been developed
as trastuzumab and pertuzumab, are approved for clinical use in and evaluated in preclinical and clinical trials99. Among them,
patients with HER2-positive breast cancer90. Recently, the HER2- capmatinib and tepotinib are approved for clinical use in
bispecific antibody zanidatamab was approved for patients treatment of patients with metastatic NSCLC harboring MET
with HER2-expressing biliary tract cancers91, and several clinical exon 14 skipping99 (Table 2).
trials for recently developed HER2-targeting monoclonal anti-
bodies are ongoing86. TRK and FLT3 inhibitors: Neurotrophic tyrosine receptor kinases
(NTRKs) are oncogenes that encode tropomyosin receptor kinase
ALK inhibitors: ALK is an receptor tyrosine kinase (RTK) with (TRK) proteins, including TRKA, TRKB, and TRKC106. TRKs are
structural homology to leukocyte tyrosine kinase (LTK), which activated by binding of intrinsic neurotrophin ligands, such as
belongs to the insulin receptor superfamily92. In normal tissues, nerve growth factor (NGF) for TRKA, brain-derived neurotrophic
ALK expression is predominant in the nervous system and is factor (BDNF) and neurotrophin 4 (NT-4) for TRKB, and neuro-
known to play an important role in physiological regulation of trophin 3 (NT-3) for TRKC106,107. NTRK gene fusion caused by
nervous system development and function92,93. Chromosomal chromosomal rearrangements of NTRK genes with various fusion
rearrangement of the ALK gene and consequent generation of a partners drives ligand-independent, constitutive activation of
fusion protein with a number of partner proteins, including TRKs, which has been found in a wide range of cancer types,
echinoderm microtubule-associated protein-like 4 (EML4), nucleo- including mammary analog secretory carcinoma, secretory breast
phosmin (NPM), tropomyosin 3 (TPM3), and tropomyosin 4 carcinoma, and infantile fibrosarcoma106,107. FLT3 (CD135), a class
(TPM4), ALK gene amplification, or ALK mutations lead to III RTK, is exclusively expressed in hematopoietic stem and
overexpression of a constitutively activated ALK protein92. ALK progenitor cell populations108. Constitutive activation of FLT3
alterations have been found in several types of cancer, such as kinase through internal tandem duplications (FLT3-ITD) or
anaplastic lymphoma, neuroblastoma, and NSCLC92. Approxi- missense mutations in the FLT3 tyrosine kinase domain109 has
mately 3–7% of patients with NSCLC, especially for those with been observed in approximately 30% of patients with acute
the adenocarcinoma subtype, have been reported to harbor ALK myeloid leukemia (AML) and a normal karyotype109,110. Several
rearrangements; ALK mutations are mutually exclusive with KRAS TKIs targeting TRKs (e.g., larotrectinib and entrectinib) or FLT3-ITD
and EGFR mutations94,95. (e.g., midostaurin, sorafenib, and gilteritinib) have been developed
Several ALK inhibitors are currently available in the clinical and approved for clinical use. Examples are listed in Table 2.
setting (Table 2), and these drugs are approved for the treatment
of NSCLC patients. Crizotinib, a first-generation ALK inhibitor, is an Inhibitors targeting PDGFR, VEGFR, or FGFR family receptors and
orally available ATP-competitive inhibitor that was clinically Ret: Tumor angiogenesis is a hallmark of cancer. Several growth
approved in 201195,96. Crizotinib was initially developed as a factors and their receptors, such as platelet-derived growth factor
MET inhibitor; however, based on the inhibitory effect of crizotinib (PDGF)/PDGFR, vascular endothelial growth factor (VEGF)/VEGFR,
on ALK at pharmacologically relevant concentrations and the fibroblast growth factor (FGF)/FGFR, stem cell factor (SCF)/c-Kit,
structural homology of the ATP-binding site between ALK and glial cell line-derived neurotrophic factor (GDNF)-family ligands/
ROS1, the clinical efficacy of crizotinib has been evaluated in rearranged during transfection (RET), and angiopoietin/Tie22,111,
patients carrying alterations in these genes95,97. Consequently, regulate the growth, differentiation and migration of cancer cells
crizotinib has been used as a first- or second-line therapy in and angiogenic activities of vascular endothelial cells22,111. PDGFs
patients with NSCLC harboring ALK, ROS1, or MET altera- are members of the ‘cysteine knot’ growth factor superfamily, the
tions96,98,99. However, due to the rapid emergence of resistance members of which contain at least three disulfide bridges and
to crizotinib and its weak ability to penetrate the central nervous forms homo- or heterodimers112. Five types of PDGF dimers

1679
(PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD) have The kinase domain of RET is similar to that of VEGFR2, and
been identified, and these PDGFs transduce signals by binding to PDGFR-α/β, c-Kit, CSF-1R, VEGFR1/2/3, Flt3, Tek, and Tie protein
two isotypes of PDGFRs (PDGFR-α and PDGFR-β)113. PDGF-AA and kinases are regulated by a similar autoinhibitory brake mechan-
PDGF-CC, ligands that bind to these PDGFRs with different ism133; multikinase inhibitors concurrently targeting these kinases
affinities, have a high affinity for PDGFR-α, whereas PDGF-BB have been developed and clinically utilized. Examples are
and PDGF-DD transduce signaling through PDGFR-β113. PDGFR-α sorafenib, sunitinib, pazopanib, lenvatinib, regorafenib, vandeta-
plays both general and specific roles in the development of nib, cabozantinib, axitinib, tivozanib, avapritinib, ripretinib,
mesenchymal and fibroblastic cell compartments; PDGFR-β plays erdafitinib, pemigatinib, infigratinib, derazantinib, futibatinib,
an important role in the formation of vascular mural cells, selpercatinib, and pralsetinib. Moreover, monoclonal antibodies
including vascular smooth muscle cells and pericytes113. Altera- (e.g., bevacizumab and ramucirumab) or recombinant proteins
tions in PDGFR-α and PDGFR-β are associated with vascular (e.g., aflibercept) have been used clinically134. Several clinically
diseases and mesenchymal cell/fibroblast-driven pathological approved inhibitors targeting these RTKs and additional angio-
conditions, respectively113. Alterations in PDGFR-α, such as point genesis inhibitors are listed in Tables 2 and 3.
mutations and amplification, exist in approximately 5% of patients
with gastrointestinal stromal tumors (GISTs) and 5–10% of patients Nonreceptor tyrosine kinase inhibitors
with glioblastoma multiforme114. BCR-ABL and SFK inhibitors: Abelson (ABL) family kinases (ABL1
The VEGF family is composed of five glycoproteins, including and ABL2) are nonreceptor tyrosine kinases that commonly
VEGFA (VEGF), VEGFB, VEGFC, VEGFD (c-Fos-induced growth contain a specific domain cassette consisting of the Src homology
factor, FIGF), and placental growth factor (PIGF or PGF)115. VEGF is 3 (SH3) domain (a protein module that binds to proline-rich
expressed as multiple alternative splicing isoforms, with pro- or sequences), the SH2 domain (a protein module that binds to
antiangiogenic effects; among them, VEGF165 is the predominant tyrosine phosphorylated sites), the tyrosine kinase domain (SH1
proangiogenic isoform that is overexpressed in various solid domain), the PXXP motif mediating interaction with SH3 domain-
tumors115,116. VEGF activates signal transduction by binding to containing proteins, and the C-terminal F-actin binding
VEGFR family receptors, VEGFR1 (FLT1), VEGFR2 (KDR), and domain135,136. ABL1, but not ABL2, additionally includes a DNA-
VEGFR3 (FLT4)25,115. VEGFR2 is primarily expressed in vascular binding domain, nuclear localization signal motifs, and nuclear
endothelial cells, and VEGF/VEGFR2 signaling plays a crucial role export signal motif and mediates DNA damage repair135,136. ABL2
in angiogenesis by controlling vascular permeability, proliferation, is mainly found at actin-rich sites, including focal adhesion and
migration, and survival of vascular endothelial cells115,117. VEGF invadopodia in the cytoplasm, through its F-actin and
also stimulates vasculogenesis in tumors by recruiting bone microtubule-binding domains and mediates cytoskeletal remodel-
marrow-derived hematopoietic progenitor cells and endothelial ing135,136. Activation of ABL kinases is tightly regulated through
progenitor cells115. VEGFC and VEGFD bind VEGFR3 and regulate autoinhibitory intramolecular interactions, intermolecular interac-
lymphangiogenesis, contributing to metastatic spread through tions with other proteins to disrupt or maintain autoinhibitory
the lymphatic system118. In addition to these angiogenic effects conformation, and posttranslational modifications such as trans-
on vascular endothelial cells, VEGF exerts several tumor- or Src-mediated tyrosine phosphorylation (e.g., activation of ABL1
promoting effects, such as increased cancer cell proliferation, by phosphorylation at Y245 and Y412), serine/threonine phos-
migration, invasion, stemness119–121, immune suppression115, and phorylation, acetylation, myristoylation, and polyubiquitina-
premetastatic niche formation122. tion135,136. Oncogenic alterations in ABLs, including fusion
The FGF family growth factors, comprising 18 members that are protein formation caused by chromosome translocations in
categorized into six subfamilies, activate signal transduction by leukemia [e.g., BCR-ABL1 in Philadelphia chromosome-positive
binding to FGFRs123. Five FGFRs (FGFR1-FGFR5) are known123,124. (Ph+) chronic myeloid leukemia (CML)] and amplification and
FGFR1-FGFR4 possess tyrosine kinase activity; in contrast, FGFR5 somatic mutations in solid tumors, constitutively activate ABL-
lacks the intracellular tyrosine kinase domain but acts as a mediated signaling pathways and promote survival, proliferation,
coreceptor of FGFR1 and modulates ligand-mediated signal- dedifferentiation, migration, and invasion in cancer cells135.
ing123–125. Heparan sulfate glycosaminoglycan (HSGAG) binds to Several kinase inhibitors targeting the BCR-ABL fusion protein
both FGF and FGFR, protecting FGFs from degradation, stabilizing have been developed and used clinically (Table 4). Imatinib is an
the interaction between ligand and receptor, and facilitating orally active first-generation BCR-ABL inhibitor. Imatinib is an ATP-
dimerization of FGF-bound FGFR123. In cancer cells, aberrant competitive type II TKI that binds to the inactive conformation of
activation of FGF/FGFR signaling caused by FGFR amplification, the ABL kinase (DFG-out conformation137)135,137. Mutation in the
activating FGFR mutations, FGFR single-nucleotide polymorph- ATP-interacting gatekeeper residue of the ATP-binding pocket
isms, FGFR fusion protein formation with various binding partners, (T315I) leads to maintenance of the active conformation of ABL
and deregulation of phospholipase Cγ1 (PLCγ1, FRS1) and FGFR and resistance to imatinib and related TKIs137. The amide
substrate 2 (FRS2) all promote cell survival, cell proliferation, substitution in the central aminophenyl ring of imatinib is crucial
angiogenesis, acquisition of an epithelial-mesenchymal transition for tyrosine kinase inhibition, and the 6-methyl residue in the
(EMT) phenotype, invasion, and metastasis in cancer cells124,126. aminophenyl ring increases selectivity for BCR-ABL137. Due to the
Similar to the aforementioned RTKs, ligand binding causes structural similarity among ABL, c-Kit, and PDGFRs (class III RTK)25,
receptor dimerization, autophosphorylation, and activation of imatinib also inhibits PDGFR and c-Kit8,135,137,138. Second-
colony-stimulating Factor 1 receptor (CSF-1R)/FMS, c-Kit/stem generation BCR-ABL inhibitors have been developed and clinically
cell factor receptor (SCFR), RET, and Tie127–130. Binding of GDNF utilized to overcome imatinib resistance caused by ABL kinase
family ligands to coreceptor GDNF family receptors (GFRα 1–4) point mutations. Nilotinib is an ATP-competitive and orally active
is required to stimulate RET kinase128. In cancer, these signaling type II kinase inhibitor with greatly improved potency compared
pathways promote the proliferation, survival, migration, and to imatinib137,138. Similar to imatinib, nilotinib inhibits the
invasion of cancer cells and angiogenesis127–130. Alterations in inactivated conformation of the ABL kinase, and resistance in
CSF-1R, c-Kit, RET, and Tie caused by overexpression, genetic the presence of BCR-ABL harboring the T315I mutation has been
mutations, gene rearrangement, and fusion protein formation reported; however, nilotinib suppresses most imatinib-resistant
have been found in various types of cancer, including clear cell BCR-ABL mutants and is not a substrate of drug influx/efflux
renal cell carcinoma (RCC, CSF-1R), GIST (c-Kit), acute myeloid transporters137–139. In addition, nilotinib displays inhibitory effects
leukemia (c-Kit), thyroid cancer (RET), and breast cancer regarding activation of multiple kinases, such as c-Kit, PDGFR, the
(Tie1)114,127,128,131,132. ABL-related kinase ARG, DDR1 kinase, oxidoreductase NQO2, and

1680
Table 3. Monoclonal antibodies or recombinant proteins that inhibit angiogenesis modulators.
Class (Target) Generic name Brand name First approved Additional indication Drug resistance Side effects/toxicity References
(Code name) (Company) indication (Year) (selected) mechanism (selected)
(selected)
229
Monoclonal Bevacizumab Avastin Metastatic CRC1 with Metastatic CRC with 5-FU- Activation of the Bleeding, pulmonary
antibody (Genentech/ standard chemotherapy based therapy (second- proangiogenic hemorrhage, proteinuria,
(VEGF) Roche) treatment (2004) line, 2006) pathway hypertension, would healing
Advanced nonsquamous Adaptation of an complications,
NSCLC2 in combination alternative mode cardiovascular toxicity,
with chemotherapy (2006) of vessel formation hypersensitivity
Metastatic RCC (2009)
Recurrent GBM3 (2009)
Metastatic cervical
cancer (2014)
Platinum-resistant
recurrent ovarian cancer in
combination with
chemotherapy (2014)
230
Monoclonal Ramucirumab Cyramza Advanced gastric Metastatic colorectal Neutropenia,
antibody (LY3009806, IMC- (Eli Lilly) cancer (2014) cancer in combination with thrombocytopenia, diarrhea,
(VEGFR2) 1121B) Aggressive NSCLC (2014) FOLFIRI5 (2015) nausea, vomiting
HCC (2019)
EGFR mutated metastatic
NSCLC (2020)
231
Recombinant Aflibercept Zaltrap, Eylea Eylea: Wet age-related Endophthalmitis,

protein (Regeneron Macular conjunctivitis, muscle
(VEGFs, VEGF- Pharmaceuticals) Degeneration (2011) volitantes, headache,
trap) Zaltrap: previously arrythmia
treated metastatic
CRC (2012)
1
2
3
GBM: glioblastoma multiforme.
4
HCC: hepatocellular carcinoma.
5
FOLFIRI: drug combination containing 5-fluorouracil, leucovorin calcium (folic acid), and irinotecan hydrochloride.

Table 4. Nonreceptor tyrosine kinase inhibitors that have been clinically used for cancer treatment.
(Code name) (Company) indication (Year) mechanism (selected)
(selected)
8,135,137,138,145,232
BCR-ABL Imatinib Gleevec Ph+1 CML2 (2001) GIST3 (2012) BCR-ABL T315I Fatigue, rashes, fluid
PDGFR (STI-571) (Novartis) Ph+ ALL4 (2013) mutation retention, bone pain,
c-Kit diarrhea
8,137,138,141,232,233
BCR-ABL Dasatinib Sprycel Ph+ ALL (2006) Ph+ CML with resistance to or BCR-ABL T315I Neutropenia,
c-Kit (BMS-354825) (Bristol-Myers intolerance of prior therapy mutation thrombocytopenia,
PDGFR Squibb) including imatinib (2009) diarrhea, rash, fluid
SFKs5 retention
137–139,141
BCR-ABL Nilotinib Tasigna Ph+ CML with resistance BCR-ABL T315I Thrombocytopenia,
c-Kit (AMN107) (Novartis) or intolerance to existing mutation myalgia, headache
PDGFR therapies (2007)
ARG
DDR1
NQO2
EPHB4

135,137,138,140
BCR-ABL Bosutinib Bosulif Ph+ CML with resistance BCR-ABL T315I Diarrhea, nausea,
SFKs5 (SKI-606) (Pfizer) or intolerance to mutation vomiting
c-Kit imatinib (2012)
PDGFR
8,142,234
BCR-ABL Radotinib6 Supect CML (2012) BCR-ABL T315I Thrombocytopenia,
PDGFR (IY-5511) (Ilyang mutation anemia, fatigue, asthenia,
Pharmaceutical) nausea, myalgia, pruritis
135,137,145
BCR-ABL Ponatinib Iclusig Resistant or intolerant BCR-ABL Diarrhea, nausea,
FLT3 (AP24534) (ARIAD CML and Ph+ ALL (2012) compound vomiting, headache
c-Kit Pharmaceuticals) mutation at
VEGFR T315, E255
PDGFR
Src
143,144,232
BCR-ABL Asciminib Scemblix Ph+ CML (2021) BCR-ABL Diarrhea, nausea
(ABL001) (Novartis) mutation at
A337, W464,
P465, V468, I502
151,152,235,236
BTK Ibrutinib Imbruvica MCL7 (2013) CML (2014) BTK C481S, Atrial fibrillation, bleeding,
(PCI-32765) (Pharmacyclics/ Waldenström’s T474I/M hypertension, diarrhea,
AbbVie/Janssen) Macroglobulinemia (2015) mutation nausea, vomiting
CLL8 (first line) and SLL9 (2016)
Relapsed/refractory MZL10 (2017)
151,152,235,236
BTK Acalabrutinib Calquence Relapsed/refractory Relapsed/refractory CLL (2019) BTK C481S Atrial fibrillation, bleeding,
(ACP-196) (Acerta Pharma/ MCL (2017) mutation hypertension, diarrhea,
AstraZeneca) nausea, vomiting
151,152,235,236
BTK Zanubrutinib Brukinsa MCL (2019) Waldenström’s BTK C481S Diarrhea, nausea,
(BGB-3111) (BeiGene) Macroglobulinemia (2021) mutation vomiting
Relapsed/refractory MZL (2021)
154,155,237
JAK Ruxolitinib Jakafi Myelofibrosis (2011) Cytopenia, diarrhea,
(INC424) (Incyte/Novartis) nausea, vomiting
1681
1682
ephrin receptor EPHB4138. Bosutinib is an orally active and ATP-
References competitive dual SFK/ABL inhibitor135,137,138 showing similar
inhibitory effects against mutated or amplified BCR-ABL associated
154,155,237
with imatinib resistance137,140 and BCR-ABL harboring the T315I
mutation137,140. Accordingly, bosutinib has been used for treat-
ment of patients with Ph+ CML who are resistant to or intolerant
of imatinib141. Other agents approved in the clinic include
radotinib, an orally active second-generation BCR-ABL inhibitor
that exhibits inhibitory effects on wild-type and some imatinib-
resistant mutant forms of BCR-ABL and PDGFR8,142, and asciminib,
an allosteric inhibitor that binds to the myristate pocket of BCR-

Diarrhea, nausea,
ABL and is effective against T315I-mutant BCR-ABL143,144. Ponati-

nib, an orally available third-generation inhibitor against both
(selected)
wild-type and T315I-mutant BCR-ABL135,137,145, also displays

vomiting
inhibitory effects on the activity of multiple kinases, including

FLT3, c-Kit, VEGFR, PDGFR, and Src145. Since 2012, ponatinib has
been used for treatment of patients with T315I-positive CML
(including accelerated phase, chronic phase, or blast phase) or
those with T315I-positive Ph+ ALL145. Additional BCR-ABL-
Drug resistance
targeting inhibitors have been developed and evaluated pre-

mechanism
clinically and clinically137.

(selected)
Src-family kinases (SFK: Blk, Fgr, Frk, Fyn, Hck, Lck, Lyn, Src, Yes,
and Yrk) contain a conserved domain organization consisting of a
myristoylated N-terminal segment (SH4 domain), followed by SH3,
SH2, linker, and tyrosine kinase domains and a short C-terminal
tail146,147. Among SFKs, Src, Fyn, and Yes are ubiquitously
expressed; Hck, Lck, Lyn, Blk, Yrk, and Fgr are primarily expressed
in hematopoietic cells and Frk-related kinases in epithelial-derived
tissues. Similar to ABL, SFKs adopt an inactive conformation
through autoinhibitory intramolecular interactions involving
phosphorylation at Y527/Y530146. Dephosphorylation of Y527/

Y530 causes destabilization of intramolecular interactions, leading
to SFK activation by interaction with RTKs, G protein-coupled
receptors, and focal adhesion kinase via its SH2 or SH3 domains
and subsequent autophosphorylation at Y416/Y419146,147. Acti-
vated SFKs play a crucial role in cell proliferation, adhesion,
migration, invasion, metastasis, angiogenesis, and therapeutic
resistance in cancer and act as key nodes of multiple oncogenic
signal transduction pathways147,148, indicating the potential of SFK
targeting for efficacious anticancer therapeutic regimens. ABL in
the active conformation is structurally similar to SFKs138,149, and
Myelofibrosis (2019)
dasatinib, which preferentially interacts with the active conforma-

indication (Year)
First approved
tion of the ABL kinase domain135,137,138, shows inhibitory effects

on SFKs149. Dasatinib targets multiple kinases, including c-Kit,
PDGFR, and SFK (Src, Fgr, Fyn, Hck, Lck, Lyn, and Yes)138,146,149, but
not BCR-ABL harboring the T315I mutation137. Currently, there are
no clinically approved anticancer regimens targeting SFKs, and
some clinical trials evaluating the effectiveness of SFK inhibitors
are still ongoing150.
(Celgene/Bristol-
BTK and JAK inhibitors: BTK is a nonreceptor tyrosine kinase that

Myers Squibb)
Brand name
plays an essential role in the development and function of B

(Company)
cells151. BTK contains five typical domains, including from the

Inrebic
N-terminus to the C-terminus the pleckstrin homology (PH) domain

Ph+: Philadelphia chromosome-positive.
required for binding to phosphatidylinositol lipids, the proline-rich

TEC homology (TH) domain, a zinc-finger motif for optimal activity
GIST: gastrointestinal stromal tumor.
CLL: chronic lymphocytic leukemia.

SLL: small lymphocytic lymphoma.
and stability of the protein, SH3 and SH2 domains, and the catalytic
ALL: acute lymphocytic leukemia.
MZL: marginal zone lymphoma.

CML: chronic myeloid leukemia.
Approved in Republic of Korea.
domain151,152. Antigen engagement by the B-cell receptor causes

Generic name
MCL: mantle cell lymphoma.

(Code name)
activation of BTK through phosphorylation at Y551 in the kinase

(SAR302503,
domain by spleen tyrosine kinase (Syk), Lyn, or Src152, which leads

TG101348)
Fedratinib
SFKs: Src-family kinases.
to subsequent autophosphorylation at Y223 in the SH3 domain

continued
and activation of downstream signaling pathways, including

phospholipase Cγ, mitogen-activated protein kinase (MAPK),
nuclear factor kappa-light-chain-enhancer of activated B cells
(NF-кB), and Akt, leading to regulation of B cell survival,
Target
proliferation, differentiation, and antibody secretion151,152 Over-

Table 4.
JAK
expression and hyperactivation of BTK have been observed in a

10
1
2
3
4
5
6
7
8
9
number of non-Hodgkin B-cell malignancies, including chronic

1683
lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), treatment. Currently available RAF inhibitors target monomeric
and mantle cell lymphoma (MCL)151,152. The Janus kinase (JAK) V600E-mutant BRAF; thus, for dimeric RAF, inhibition of one
family comprises the nonreceptor tyrosine kinases JAK1, JAK2, protomer by the drug paradoxically leads to transactivation of the
JAK3, and TYK2153,154. Cytokine binding to receptors leads to other protomer and downstream signaling157. Therefore, a
receptor dimerization and recruitment, trans-autophosphorylation, combination of MEK inhibitors (e.g., vemurafenib plus cobimeti-
and activation of JAK, resulting in phosphorylation and activation nib, dabrafenib plus trametinib, and encorafenib plus binimetinib)
of downstream signaling cascades such as phosphatidylinositol-3- has been clinically utilized168. Examples of clinically approved
kinase (PI3K)/Akt, MAPK, and signal transducer and activator of BRAF and MEK inhibitors are listed in Table 5.
transcription (STAT) transcription factors153–155. Deregulation of
JAK through hyperactivation and activating mutations (e.g., JAK2 PI3K/mTOR inhibitors: The PI3K/Akt/mTOR pathway plays a
V617F) has been reported in myeloproliferative neoplasms, central role in regulating cell proliferation, survival, growth, and
including myelofibrosis154. Examples of clinically approved inhibi- metabolism158,169. Deregulation of the PI3K/Akt/mTOR pathway
tors targeting BTK (e.g., ibrutinib, acalabrutinib, and zanubrutinib) through mutation or amplification of PIK3CA (encoding the
or JAK (e.g., ruxolitinib and fedratinib) are listed in Table 4. p110α subunit of PI3K), loss or inactivation of phosphatase and
tensin homolog (PTEN), and hyperactivation of mTOR have been
Inhibitors targeting downstream signaling pathways: RAS inhibitor commonly found in various cancer types158,169 and related
and serine/threonine kinase inhibitors. Activated tyrosine kinases anticancer drug resistance158,170. Hence, inhibitors targeting
trigger phosphorylation and activation of downstream signaling PI3K, Akt, and mTOR have been evaluated in preclinical studies
mediators that are mostly serine/threonine kinases. The main and clinical trials, and some inhibitors have been used clinically
relevant downstream signaling pathways are the PI3K/Akt/ for cancer treatment.
mammalian target of rapamycin (mTOR) and RAS/RAF/MEK/ERK Because of the specific expression of PI3K, p110γ, and p110δ
pathways. Alterations in several components of these pathways subunits in the hematopoietic system, the association of the PI3K
(e.g., RAS, RAF, MEK, and PI3K) have been found in various types pathway with regulating B-cell receptor (BCR) signaling, and the
of cancer and thus considered druggable targets156–158. Cyclins undesirable toxicity of pan-PI3K or dual PI3K/mTOR inhibi-
are also downstream effector molecules of these signaling tors171,172, PI3K inhibitors that specifically target PI3Kδ or PI3Kγ
cascades and play an important role in regulating cell cycle have been employed for treatment of patients with lymphoma.
progression and various cellular processes, such as gene Some mTOR inhibitors, especially rapamycin analogs (rapalogs)
transcription, DNA damage repair, and metabolism, by associat- that form a complex with FK506-binding protein 12 (FKBP12) and
ing with cyclin-dependent kinases (CDKs)159. Alterations in inhibit mTORC1 (but not mTORC2) activity, have been approved
cyclins and CDKs have been observed in various cancer types, for clinical use8. Additionally, ATP-competitive mTOR inhibitors
and several CDK inhibitors have been developed and approved have been developed and are under preclinical and clinical
for clinical use160. Examples of these targeted therapeutic drugs evaluation8. Examples of clinically utilized PI3K (e.g., idelalisib,
are described below. duvelisib, copanlisib and alpelisib) and mTOR inhibitors (e.g.,
sirolimus, temsirolimus, and everolimus) are listed in Table 5.
RAS/RAF/MEK inhibitors: RAS is a guanine nucleotide-binding
protein that plays an important role in cell proliferation and CDK inhibitors: Among more than 20 members of CDK family
differentiation, and farnesylation of RAS by RAS farnesyltransferase proteins159, CDK4 and CDK6 (in complex with cyclin D) play a
(FTase) is crucial for RAS to associate with membranes and its crucial role in promoting cell cycle progression by sequestering
transforming activity161. Mutations in RAS result in constitutive CDK inhibitors and inducing various proteins involved in cell
activation161. Among the three RAS isoforms (KRAS, HRAS, and cycle progression from G1 to S phase, DNA replication, chromatin
NRAS), KRAS is the most frequently mutated isoform, and five structure, chromosome segregation, and the spindle assembly
mutations (G12D, G12V, G12C, G13D, and Q61R) are the most checkpoint through phosphorylation of various targets, including
prominent RAS mutations observed in cancer patients156. Based retinoblastoma protein (RB), and activating E2F-mediated tran-
on the important role of RAS FTase in the regulation of RAS scription160. Hence, CDK4/6 has been considered attractive] for
transforming activity, several FTase inhibitors have been devel- targeted anticancer therapy. Three CDK4/6 inhibitors have been
oped and evaluated, yet none of them have been clinically used used clinically for treatment of patients with HR-positive
because of limited efficacy162. Recently, a small molecule inhibitor advanced breast cancer (Table 5). Palbociclib, ribociclib, and
targeting mutated KRAS (KRASG12C) was developed and approved abemaciclib are orally available, reversible, and selective CDK4/6
for clinical use. Sotorasib is an orally available inhibitor that binds inhibitors that have been used clinically in combination with an
to inactive guanosine diphosphate (GDP)-bound KRAS via a aromatase inhibitor for treatment of postmenopausal women
covalent bond between the C12 residue and the acrylamide with ER-positive and HER2-negative advanced or metastatic
warhead and noncovalent bonds between the isopropylpyridine breast cancer8,173,174.
substituent and a cryptic pocket comprising H95, Y96, and Q99
residues; this results in inhibition of KRASG12C without affecting Other targeted anticancer agents. In addition to PARP inhibitors,
wild-type KRAS163,164. Another KRASG12C inhibitor, adagrasib other types of clinically used or recently approved targeted
(MRTX849), is under clinical trial evaluation165. therapies, including epigenetic modulators (e.g., DNA methyl-
Activated RAS in the GTP-bound state leads to association of transferase inhibitors, histone deacetylase inhibitors, EZH2
RAF proteins, causing formation of RAF homo- or heterodimers, inhibitors, and isocitrate dehydrogenase inhibitors), proteasome
RAF phosphorylation, and consequent activation of the down- inhibitors, Bcl-2 inhibitors, and smoothened inhibitors, are
stream signaling mediators MEKs and ERKs157,166. Among the summarized in Table 6.
three isoforms of RAF (ARAF, BRAF, and CRAF), mutations in BRAF,
especially at the V600 residue (e.g., V600E) in the activation loop, PARP inhibitors: The PARP family plays a crucial role in
are frequently observed in several types of cancer, including regulating DNA repair processes upon the DNA damage response
melanoma, papillary thyroid cancer, and colorectal can- (DDR) and chromatin modulation175,176. PARP family proteins,
cer157,166,167. Indeed, the V600E mutation, which causes RAS- especially PARP1 and PARP2, bind to DNA lesions and mediate
independent activation of BRAF, accounts for more than 90% of poly-ADP ribosylation (PARylation) of chromatin and DNA damage
BRAF mutation cases in cancer157,166,167. Thus far, three RAF response components, resulting in DNA repair by recruiting DNA
inhibitors and three MEK inhibitors have been used for anticancer repair effectors such as XRCC1175,176. After autoPARylation, PARP

1684
Table 5. Serine/threonine kinase inhibitors that have been clinically used for cancer treatment.
Target Generic name Brand name First approved indication (Year) Additional indication Drug resistance Side effects/toxicity References
(Code name) (Company) mechanism (selected)
(selected)
163,164,238
KRAS Sotorasib Lumakras Locally advanced or metastatic NSCLC BRAF/RAS Nausea, vomiting,
(AMG 510) (Amgen) harboring G12C-mutant KRAS with at mutation diarrhea, elevated
least one prior systemic therapy (2021) KRAS G12V, aminotransferase
G13D mutation level, fatigue,
arthralgia
157,167,168,239–241
BRAF Vemurafenib Zelboraf Melanoma harboring V600E-mutant Advanced melanoma NRAS mutation Rash, diarrhea,
(PLX4032) (Genentech) BRAF (2011) with BRAF mutation in CRAF fatigue, arthralgia
combination with overexpression
cobimetinib (2015) secondary BRAF
mutation
MEK1/2
mutation
157,167,168,239–241
BRAF Dabrafenib Tafinlar or Rafinlar Melanoma harboring V600E-mutant Advanced melanoma NRAS mutation Rash, diarrhea,
(GSK2118436) (Novartis/ BRAF (2013) with BRAF mutation in CRAF fatigue, arthralgia
GlaxoSmithKline) combination with overexpression
trametinib (2014) secondary BRAF
BRAF V600E-mutant mutation
metastatic NSCLC1 in MEK1/2
combination with mutation
trametinib (2017)
BRAF V600E-mutant
anaplastic thyroid cancer
in combination with
trametinib (2018)
157,167,168,239–241
BRAF Encorafenib Braftovi Unresectable or metastatic melanoma BRAF V600E-mutant NRAS mutation Rash, diarrhea,
(LGX818) (Novartis/Array with BRAF mutations in combination metastatic CRC2 in CRAF fatigue, arthralgia
BioPharma) with binimetinib (2018) combination with overexpression
cetuximab (2020) secondary BRAF
mutation
MEK1/2
mutation
157,167,168,239–241
MEK Trametinib Mekinist BRAF V600E-mutant advanced Advanced melanoma RTK reactivation Rash, diarrhea,
(GSK1120212, (GlaxoSmithKline/ melanoma (2013) with BRAF mutation in PI3K, STAT3 fatigue, arthralgia
JTP-74057) Novartis) combination with activation
dabrafenib (2014)
BRAF V600E-mutant
metastatic NSCLC1 in
combination with
dabrafenib (2017)
BRAF V600E-mutant
anaplastic thyroid cancer
in combination with
dabrafenib (2018)
157,167,168,239–242
MEK Cobimetinib Cotellic Advanced melanoma with BRAF RTK reactivation Rash, diarrhea,
(GDC-0973, (Genentech) mutation in combination with PI3K/STAT3 fatigue, arthralgia
RG7420) vemurafenib (2015) activation

Table 5. continued
Target Generic name Brand name First approved indication (Year) Additional indication Drug resistance Side effects/toxicity References
(Code name) (Company) mechanism (selected)
(selected)
157,167,168,239–241
MEK Binimetinib Mektovi Unresectable or metastatic melanoma RTK reactivation Rash, diarrhea,
MEK162, ARRY- (Array Biopharma) with BRAF mutations in combination PI3K/STAT3 fatigue, arthralgia
162, ARRY- with encorafenib (2018) activation
438162)
157,167,168,239–241
MEK Selumetinib Koselugo Neurofibromatosis type 1 plexiform RTK reactivation Rash, diarrhea,
(AZD6244, (Array Biopharma/ neurofibroma (2020) PI3K/STAT3 fatigue, arthralgia
ARRY-142886) AstraZeneca) activation
171,172,243,244
PI3Kδ Idelalisib Zydelig Relapsed CLL3 (2014) RTK reactivation Hyperglycemia, rash,
(CAL-101, GS- (Gilead Sciences) stomatitis, fatigue,
1101) nausea, diarrhea
171,172,243,244
PI3Kγ Duvelisib Copiktra Relapsed or refractory CLL, SLL4, and Isoform Hyperglycemia, rash,
PI3Kδ (IPI-145, (Intellikine/ FL5 (2018) switching stomatitis, fatigue,
INK1197) Secura Bio) Akt/mTOR nausea, diarrhea
activation

Loss of PTEN
171,172,243,244
pan- Copanlisib Aliqopa Relapsed or refractory FL (2017) RTK reactivation Hyperglycemia, rash,
PI3K (BAY 80–6946) (Bayer) stomatitis, fatigue,
(p110α nausea, diarrhea
and
p110δ)
171,172,243,244
PI3Kα Alpelisib Piqray HR+ and HER2- advanced/metastatic RTK reactivation Hyperglycemia, rash,
(NVP-BYL719) (Novartis) breast cancer with a PIK3CA mutation stomatitis, fatigue,
with prior endocrine therapy nausea, diarrhea
(in combination with fulvestrant, 2019)
171,172,243,244
mTOR Sirolimus Rapamune Lymphangioleiomyomatosis (2015) Locally advanced RTK reactivation Hyperglycemia, rash,
(AY-22989, (Pfizer) unresectable or stomatitis, fatigue,
rapamycin) metastatic malignant nausea, diarrhea
perivascular epithelioid
cell tumor (2021)
171,172,243,244
mTOR Temsirolimus Torisel Advanced RCC6 (2007) RTK reactivation Hyperglycemia, rash,
(CCI-779) (Pfizer) stomatitis, fatigue,
nausea, diarrhea
171,172,243,244
mTOR Everolimus Afinitor RCC after failure of sunitinib or sorafenib Advanced pancreatic RTK reactivation Hyperglycemia, rash,
(RAD001) (Novartis) treatment (2009) neuroendocrine stomatitis, fatigue,
tumor (2011) nausea, diarrhea
HR+ and HER2- breast
cancer for use in
combination with
exemestane (2012)
Subependymal giant-cell
astrocytoma (2012)
8,173,245
CDK4/6 Palbociclib Ibrance Advanced or metastatic breast HR+ and HER2- CDK4/6 Fatigue, nausea,
(PD 0332991) (Pfizer) cancer (2015) metastatic breast overexpression diarrhea, vomiting
cancer (2016)
8,174,245
CDK4/6 Ribociclib Kisqali HR+ and HER2- metastatic breast CDK4/6 Fatigue, nausea,
(LEE011) (Novartis) cancer (2017) overexpression diarrhea, vomiting
1685
1686
dissociates from DNA, and the DNA repair process is completed by
References recruitment of DNA repair proteins176. BReast CAncer gene 1
(BRCA1) and BRCA2 (BRCA1/2) are tumor-suppressor genes that
8,245,246
play a key role in repair of double-strand DNA breaks via the
conservative homologous recombination repair (HRR) pro-
cess175,177. Mutations in BRCA1/2 genes have been found in
some cancer types, including breast, ovarian, pancreatic, and
prostate cancers177. Defects in BRCA function due to BRCA1/2
diarrhea, vomiting
gene mutations cause loss of the HRR process and mediate the
Fatigue, nausea,
DNA repair process in a nonconservative manner, such as

nonhomologous end joining, leading to DNA alteration175. As
(selected)
BRCA mutant cancer cells are vulnerable to blockade of the DNA

repair process, treatment of BRCA-deficient cells with PARP
inhibitors leads to unsustainable genomic instability and cancer
cell death176. This synthetic lethal interaction between PARP
blockade and BRCA1/2 mutation suggests a therapeutic strategy
targeting PARP for treatment of cancer types harboring BRCA
Drug resistance
overexpression
mutations. Based on these findings, some orally available PARP

mechanism
inhibitors, such as olaparib, rucaparib, niraparib, and talazoparib,

(selected)
have been clinically used for treatment of BRCA-mutated cancers,

CDK4/6
including ovarian, breast, and prostate cancers (Table 6)8,178.

Additional investigations to evaluate the effectiveness of combi-
natorial treatment with chemotherapeutic agents, PI3K inhibitors,
and anticancer immunotherapy have been conducted in pre-
cancer with a high risk of
clinical and clinical settings178.

recurrence and a Ki-67
HR+, HER2-, and node-
positive early breast
score ≥20% (2021)
Summary and future perspectives in the development of

molecular targeted therapy
Owing to advances in molecular diagnosis, genome-wide
analysis, and in-depth understanding of cancer biology, numer-
ous tyrosine kinase inhibitors have recently been developed,
tested preclinically and clinically, and utilized for cancer
treatment in the clinic. Nevertheless, poor efficacy, toxicity, and
tumor relapse due to drug resistance are major obstacles for
HR+ and HER2- advanced or metastatic
targeted therapy-based efficacious anticancer treatment. There-

fore, further investigation is required to develop efficacious
First approved indication (Year)
personalized targeted therapies that overcome drug resistance

and reduce side effects and toxicity.
To this end, a fundamental template for drug discovery by
identifying additional druggable targets through in-depth bio-
chemical, genomic, and molecular studies and structural investi-
breast cancer (2017)
gations is needed. Drug discovery with different chemical entities

or modes of action is also necessary for the development of
molecular targeted therapy. In addition to direct or allosteric
modulation of cellular targets, strategies for indirect manipulation
of cellular targets [e.g., posttranslational modification179 or
targeted protein degradation using proteolysis-targeting chimera
(PROTAC)180] based on biological and functional studies for
cancer-specific modulation would be applicable. Furthermore,
the development of small molecule inhibitors that concurrently
block signaling pathways associated with cancer cell proliferation
and drug resistance and design of optimized combinatorial
Brand name
(Company)
therapeutic strategies using molecular targeted therapy, either

Verzenio
(Eli Lilly)
alone or in combination with other types of anticancer therapy

(e.g., chemotherapy and immune checkpoint inhibitors), would be
of importance for increased efficacy, limited toxicity, and minimal
SLL: small lymphocytic lymphoma.
drug resistance.
Because the side effects and toxicity of targeted therapy are
Generic name
(Code name)
mediated by nonspecific inhibition of the same target in normal

Abemaciclib
(LY2835219)
RCC: renal cell carcinoma.
cells10, strategies for cancer cell-specific targeting are also

FL: follicular lymphoma.
important. A relevant example is the recent development of

continued
KRASG12C inhibitors. Since the clinical failure of farnesyltransferase

inhibitors, KRAS has been considered an undruggable target181. In
a recent study utilizing the high reactivity of cysteine, compounds
that covalently bind to KRAS via the mutated cysteine residue and
CDK4/6
Target
allosterically inhibit GTP binding to KRAS were designed182; this

Table 5.
approach can inhibit KRAS without occupying the GTP/GDP-

1
2
3
4
5
6
binding pocket on the surface and achieve specificity for mutant

Table 6. Additional targeted therapies that have been clinically used for cancer treatment.
Target Generic name Brand name First approved Additional indication Drug resistance Side effects/toxicity (selected) References
(Code name) (Company) indication (Year) mechanism
(selected)
8,178,247
PARP Olaparib Lynparza Advanced ovarian Maintenance treatment of Restoration of Ileus, myelodysplastic
(AZD2281) (AstraZeneca) cancer (2014) ovarian cancer (2017, homologous syndrome, interstitial lung
2018, 2020) recombination repair disease
BRCA-mutated metastatic and ADP-ribosylation
breast cancer (2018, 2022) (PARylation)
Metastatic pancreatic cancer reversion mutations
(2019, 2020)
8,178,247
PARP Rucaparib Rubraca Advanced ovarian Maintenance treatment of Restoration of Nausea, vomiting, diarrhea,
(AG014699) (Clovis Oncology) cancer (2016) ovarian cancer (2018) homologous constipation, red blood cell
recombination repair count decrease,
and ADP-ribosylation photosensitivity, renal
(PARylation) impairment, dysgeusia
reversion mutations
8,178,247
PARP Niraparib Zejula Recurrent ovarian Maintenance treatment for Restoration of Nausea, constipation, platelet/

(MK-4827) (Tesaro) cancer (2017) patients with platinum- homologous red blood cells count decrease,
responsive ovarian cancer recombination repair lymphangioleiomyomatosis
regardless of biomarker and ADP-ribosylation
status (2020) (PARylation)
reversion mutations
8,178,247
PARP Talazoparib Talzenna BRCA1/2-mutated Restoration of Hematopoietic erythropenia,
(BMN-673) (Pfizer) advanced or homologous anemia, thrombocytopenia,
metastatic HER2- recombination repair pancytopenia, neutropenia
breast cancer (2018) and ADP-ribosylation
(PARylation)
reversion mutations
8,247,248
DNMT1 Azacitidine Vidaza MDS2 (2004) Adaptive responses Fatigue, constipation, mucositis,
(5-azacytidine) (Pharmion of the pyrimidine pneumonia, febrile neutropenia
Corporation) metabolism network
8,247,249
DNMT Decitabine Dacogen Dacogen Inqovi: MDS in combination Adaptive responses Fatigue, constipation, mucositis,
(NSC 127716) (Janssen-Cilag/ : MDS (2006) with cedazuridine (2020) of the pyrimidine pneumonia, febrile neutropenia
Otsuka metabolism network

Pharmaceutical)
Inqovi (oral tablet)
(Otsuka
Pharmaceutical)
250,251
HDAC3 Vorinostat Zolinza Relapse/refractory Overexpression of Diarrhea, fatigue, nausea,
(SAHA) (Merck) CTCL4 (2006) Bcl-2 family proteins anorexia, dysgeusia,
JAK/STAT3 pathways thrombocytopenia, pulmonary
HDAC alterations embolism, cardiac
Epigenetic alterations abnormalities
Protection of
oxidative stress
Alterations in
apoptosis/autophagy
1687
1688
Table 6. continued
(selected)
250,251
HDAC Romidepsin Istodax CTCL (2009) PTCL5 (2011) P-glycoprotein- Thrombocytopenia, anemia,
(FK228, (Celgene Corp./ mediated drug efflux neutropenia, fatigue, nausea,
FR901228) Bristol-Myers HDAC alterations vomiting, anorexia, tumor lysis
Squibb) Epigenetic alterations syndrome
Protection of
oxidative stress
Alterations in
apoptosis/autophagy
250,251
HDAC Belinostat Beleodaq PTCL (2014) HDAC alterations Nausea, vomiting, tumor lysis
(PXD-101) (Spectrum Epigenetic alterations syndrome, hepatic failure,
Pharmaceuticals) Alterations in cardiac abnormalities
apoptosis/autophagy
250,251
HDAC Panobinostat Farydak MM7 (2015) HDAC alterations Severe diarrhea, nausea,
(LBH-589) (Novartis/ Epigenetic alterations vomiting, cardiac abnormalities
Secura Bio) Protection of
oxidative stress
Alterations in
apoptosis/autophagy
252
EZH26 Tazemetostat Tazverik Relapsed/refractory Metastatic or locally advanced EZH2 Y726F, C663Y Nausea, asthenia, fatigue,
(E7438/ (Epizyme) follicular epithelioid sarcoma (2020) mutation alopecia, dry skin, diarrhea,
EPZ6438) lymphoma (2020) neutropenia,

thrombocytopenia
8,91,216,253
IDH18 Ivosidenib Tibsovo Relapse/refractory Frontline in AML patients with Elevated QT interval prolongation, IDH
(AG-120) (Servier AML9 with an IDH1 comorbidities (2019) 2-hydroxyglutarate differentiation syndrome,
Pharmaceuticals) mutation (2018) IDH1-mutated Hypermethylation anemia, thrombocytopenia
cholangiocarcinoma (2021)
216,253
IDH2 Enasidenib Idhifa Relapse/refractory Elevated Hyperbilirubinemia,
(AG-221) (Agios AML with an IDH2 2-hydroxyglutarate thrombocytopenia,
Pharmaceuticals) mutation (2017) Hypermethylation IDH differentiation syndrome
254,255
Proteasome Bortezomib Velcade Relapse/refractory Proteasome Peripheral neuropathy,
(PS-341) (Millennium/ MM (2003) mutation/ hematologic toxicities, diarrhea,
Takeda/Janssen overexpression fatigue, dyspnea, zoster
Pharmaceutical) Heat shock protein reactivation
upregulation
Autophagy
Increased drug efflux
Alterations in
glutathione
metabolism
254,255
Proteasome Carfilzomib Kyprolis Advanced Proteasome mutation Hematologic toxicities,
(PR-171) (Onyx MM (2012) Autophagy pneumonia, hyponatremia,
Pharmaceuticals) Increased drug efflux fatigue, hypophosphatemia,
infusion reactions, chest pain,
heart failure
254,255
Proteasome Ixazomib Ninlaro MM (2015) Proteasome mutation Hematologic toxicities, fatigue,
(MLN2238) (Takeda) Autophagy rash, decreased appetite,
diarrhea, vomiting

Table 6. continued
(selected)
8,256
Bcl-2 Venetoclax Venclexta CLL10 (2016) AML (2018) BCL2 mutation Bone marrow suppression,
(ABT-199) (AbbVie/ Activation of the nausea, vomiting, diarrhea
Genentech) MAPK/Akt pathway
Deregulation of
energy metabolism
Interaction with
stromal cells
8,257
Smoothened Vismodegib Erivedge BCC11 (2012) SMO mutations Muscle spasm, weight loss,
(GDC-0449) (Genentech/ (e.g., D473H) alopecia, dysgeusia
Roche) SUFU/GLI2 copy
number variation/
mutation
8,257
Smoothened Sonidegib Odomzo Locally advanced SMO mutations Nausea, dysgeusia, anorexia,
(NVP-LDE225) (Novartis) BCC (2015) SUFU/GLI2 copy muscle spasm, fatigue, creatine

number variation/ kinase elevation
mutation
8,257
Smoothened Glasdegib Daurismo AML (2018) SMO mutations Thrombocytopenia, anorexia,
(PF-04449913) (Pfizer) SUFU/GLI2 copy peripheral edema, fatigue,
number variation/ neutropenia
mutation
1
DNMT: DNA methyltransferase.
2
MDS: myelodysplastic syndrome.
3
HDAC: histone deacetylase.
4
CTCL: cutaneous T-cell lymphoma.
5
PTCL: peripheral T-cell lymphoma.
6
EZH2: enhancer of zeste homolog 2.
7
MM: multiple myeloma.
8
IDH: isocitrate dehydrogenase.
9
AML: acute myeloid leukemia.
10
11
BCC: basal cell carcinoma.

12
ALCL: anaplastic large cell lymphoma.
1689
1690
KRAS beyond wild-type KRAS, thus avoiding the unfavorable 17. Colomer, R. et al. When should we order a next generation sequencing test in a
effects caused by inhibition of wild-type KRAS182,183. Based on this patient with cancer? EClinicalMedicine 25, 100487 (2020).
innovative study and a better understanding of the crystal 18. Dillman, R. O. Perceptions of Herceptin: a monoclonal antibody for the treat-
structure of mutant KRAS, several potent KRASG12C inhibitors have ment of breast cancer. Cancer Biother. Radiopharm. 14, 5–10 (1999).
19. Cohen, M. H. et al. Approval summary for imatinib mesylate capsules in the
been developed and approved for clinical use183,184; agents
treatment of chronic myelogenous leukemia. Clin. Cancer Res. 8, 935–942 (2002).
targeting other types of mutant KRAS, such as KRASG12D, have also 20. Zahavi, D. & Weiner, L. Monoclonal antibodies in cancer therapy. Antibodies 9, 34
been developed and evaluated in preclinical settings185,186. (2020).
Studies on molecular diagnosis and discovery of predictive 21. Bhullar, K. S. et al. Kinase-targeted cancer therapies: progress, challenges and
biomarkers are necessary to properly select eligible populations future directions. Mol. Cancer 17, 48 (2018).
for better efficacy and reduced toxicity183. Several newly devel- 22. Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell
oped approaches, such as next-generation sequencing technol- 144, 646–674 (2011).
ogy187, whole-genome sequencing188, and machine learning189, 23. Cohen, P., Cross, D. & Jänne, P. A. Kinase drug discovery 20 years after imatinib:
can be applied to this end. In fact, artificial intelligence (AI)-based progress and future directions. Nat. Rev. Drug Discov. 20, 551–569 (2021).
24. Du, Z. & Lovly, C. M. Mechanisms of receptor tyrosine kinase activation in cancer.
strategies190 are expected to be extensively utilized for the design
Mol. Cancer 17, 58 (2018).
of the structure and chemical synthetic procedures, identification 25. Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell
of potential hits, prediction of pharmacokinetic profiles, assess- 141, 1117–1134 (2010).
ment of side effects and toxicity, and drug repurposing. 26. Roskoski, R. Jr. Classification of small molecule protein kinase inhibitors based
Finally, emerging evidence has shown the role of the host upon the structures of their drug-enzyme complexes. Pharmacol. Res. 103,
microbiome in cancer development and progression, drug 26–48 (2016).
responsiveness, and therapy-induced side effects191,192. For 27. Lu, X., Smaill, J. B. & Ding, K. New promise and opportunities for allosteric kinase
example, the gut microbiome promotes the function of mutant inhibitors. Angew. Chem. Int. Ed. Engl. 59, 13764–13776 (2020).
p53 toward oncogenicity193 and modulates responsiveness to 28. Okamoto, K. et al. Distinct binding mode of multikinase inhibitor lenvatinib
revealed by biochemical characterization. ACS Med. Chem. Lett. 6, 89–94
antitumor therapy such as anti-PD-1 immunotherapy194. A
(2015).
number of investigations into the influence of the gut microbiome 29. Li, J. Y., Chen, Y. P., Li, Y. Q., Liu, N. & Ma, J. Chemotherapeutic and targeted
on chemotherapy and anticancer immunotherapy are ongoing; agents can modulate the tumor microenvironment and increase the efficacy of
however, the effect of the host microbiome on molecular targeted immune checkpoint blockades. Mol. Cancer 20, 27 (2021).
therapy remains elusive. Further studies are necessary to 30. Kersh, A. E. et al. Targeted therapies: immunologic effects and potential appli-
investigate the role of the host microbiome in the efficacy and cations outside of cancer. J. Clin. Pharmacol. 58, 7–24 (2018).
toxicity of molecular targeted therapy and to identify key factors 31. Joly, E. & Hudrisier, D. What is trogocytosis and what is its purpose? Nat.
to develop safer and more efficacious therapeutic strategies based Immunol. 4, 815 (2003).
on microbiome-targeted therapy. 32. Miyake, K. & Karasuyama, H. The role of trogocytosis in the modulation of
immune cell functions. Cells 10, 1255 (2021).
In summary, the present paper briefly reviews the current status
33. Matlung, H. L. et al. Neutrophils kill antibody-opsonized cancer cells by tro-
of molecular targeted therapy and discusses future directions, goptosis. Cell Rep. 23, 3946–3959 (2018).
providing novel therapeutic strategies with better efficacy and 34. Hsu, Y. F. et al. Complement activation mediates cetuximab inhibition of non-
safety to improve the prognosis of cancer patients. small cell lung cancer tumor growth in vivo. Mol. Cancer 9, 139 (2010).
35. Lizotte, P. H. et al. A high-throughput immune-oncology screen identifies EGFR
inhibitors as potent enhancers of antigen-specific cytotoxic T-lymphocyte tumor
REFERENCES cell killing. Cancer Immunol. Res. 6, 1511–1523 (2018).
1. Sung, H. et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence 36. Donia, M. et al. BRAF inhibition improves tumor recognition by the immune
and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 71, system: potential implications for combinatorial therapies against melanoma
209–249 (2021). involving adoptive T-cell transfer. Oncoimmunology 1, 1476–1483 (2012).
2. Ke, X. & Shen, L. Molecular targeted therapy of cancer: the progress and future 37. Ayeni, D. et al. Tumor regression mediated by oncogene withdrawal or erlotinib
prospect. Front. Lab. Med. 1, 69–75 (2017). stimulates infiltration of inflammatory immune cells in EGFR mutant lung
3. Jemal, A. et al. Annual report to the nation on the status of cancer, 1975–2005, tumors. J. Immunother. Cancer 7, 172 (2019).
featuring trends in lung cancer, tobacco use, and tobacco control. J. Natl Cancer 38. Ellis, L. M. & Hicklin, D. J. Resistance to targeted therapies: refining anticancer
Inst. 100, 1672–1694 (2008). therapy in the era of molecular oncology. Clin. Cancer Res. 15, 7471–7478
4. Saini, K. S. & Twelves, C. Determining lines of therapy in patients with solid (2009).
cancers: a proposed new systematic and comprehensive framework. Br. J. 39. Hou, J. et al. Evolution of molecular targeted cancer therapy: mechanisms of
Cancer 125, 155–163 (2021). drug resistance and novel opportunities identified by CRISPR-Cas9 screening.
5. Usborne, C. M. & Mullard, A. P. A review of systemic anticancer therapy in Front. Oncol. 12, 755053 (2022).
disease palliation. Br. Med. Bull. 125, 43–53 (2017). 40. Rebecca, V. W. & Herlyn, M. Nongenetic mechanisms of drug resistance in
6. Lind, M. J. Principles of systemic anticancer therapy. Medicine 44, 20–24 (2016). melanoma. Annu. Rev. Cancer Biol. 4, 315–330 (2020).
7. Jones, R. Cytotoxic chemotherapy: clinical aspects. Medicine 44, 25–29 (2016). 41. Marusyk, A., Janiszewska, M. & Polyak, K. Intratumor heterogeneity: the rosetta
8. Zhong, L. et al. Small molecules in targeted cancer therapy: advances, chal- stone of therapy resistance. Cancer Cell 37, 471–484 (2020).
lenges, and future perspectives. Signal Transduct. Target. Ther. 6, 201 (2021). 42. Turner, N. C. & Reis-Filho, J. S. Genetic heterogeneity and cancer drug resistance.
9. Charlton, P. & Spicer, J. Targeted therapy in cancer. Medicine 44, 34–38 (2016). Lancet Oncol. 13, e178–e185 (2012).
10. Peters, G. J. From ‘targeted therapy’ to targeted therapy. Anticancer Res. 39, 43. Meador, C. B. & Hata, A. N. Acquired resistance to targeted therapies in NSCLC:
3341–3345 (2019). updates and evolving insights. Pharmacol. Ther. 210, 107522 (2020).
11. Abraham, J. & Staffurth, J. Hormonal therapy for cancer. Medicine 44, 30–33 44. Li, X. et al. The multi-molecular mechanisms of tumor-targeted drug resistance
(2016). in precision medicine. Biomed. Pharmacother. 150, 113064 (2022).
12. Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: 45. Wheeler, D. L., Dunn, E. F. & Harari, P. M. Understanding resistance to EGFR
from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–658 inhibitors-impact on future treatment strategies. Nat. Rev. Clin. Oncol. 7,
(2020). 493–507 (2010).
13. Keefe, D. M. K. & Bateman, E. H. Potential successes and challenges of targeted 46. Ni, Y. et al. The role of tumor-stroma interactions in drug resistance within tumor
cancer therapies. J. Natl Cancer Inst. Monogr. 2019, lgz008 (2019). microenvironment. Front. Cell Dev. Biol. 9, 637675 (2021).
14. Lee, Y. T., Tan, Y. J. & Oon, C. E. Molecular targeted therapy: treating cancer with 47. Liu, Y., Duan, C. & Zhang, C. E3 ubiquitin ligase in anticancer drugdsla resistance:
specificity. Eur. J. Pharmacol. 834, 188–196 (2018). recent advances and future potential. Front. Pharmacol. 12, 645864 (2021).
15. Habeeb, N. W.-A. et al. The use of targeted therapies for precision medicine in 48. Qin, S. et al. Emerging role of tumor cell plasticity in modifying therapeutic
oncology. Clin. Chem. 62, 1556–1564 (2016). response. Signal Transduct. Target. Ther. 5, 228 (2020).
16. Valent, P. et al. Paul Ehrlich (1854–1915) and his contributions to the foundation 49. Roger, S. et al. Adverse events of targeted therapies reported by patients with
and birth of translational medicine. J. Innate Immun. 8, 111–120 (2016). cancer treated in primary care. Eur. J. Gen. Pract. 26, 202–209 (2020).

1691
50. Widakowich, C., de Castro, G. Jr., de Azambuja, E., Dinh, P. & Awada, A. Review: 83. Tsang, R. Y., Sadeghi, S. & Finn, R. S. Lapatinib, a dual-targeted small molecule
side effects of approved molecular targeted therapies in solid cancers. Oncol- inhibitor of EGFR and HER2, in HER2-amplified breast cancer: from bench to
ogist 12, 1443–1455 (2007). bedside. Clin. Med. Insights: Ther. 3, CMT.S3783 (2011).
51. Fabbrocini, G., Panariello, L., Caro, G. & Cacciapuoti, S. Acneiform rash induced 84. Martin, M. & S. López-Tarruella. Emerging therapeutic options for HER2-positive
by EGFR inhibitors: review of the literature and new insights. Ski. Appendage breast cancer. Am. Soc. Clin. Oncol. Educ. Book, e64–e70 (2016).
Disord. 1, 31–37 (2015). 85. Kulukian, A. et al. Preclinical activity of HER2-selective tyrosine kinase inhibitor
52. Liu, S. & Kurzrock, R. Toxicity of targeted therapy: implications for response and tucatinib as a single agent or in combination with trastuzumab or docetaxel in
impact of genetic polymorphisms. Cancer Treat. Rev. 40, 883–891 (2014). solid tumor models. Mol. Cancer Ther. 19, 976–987 (2020).
53. Assoun, S., Lemiale, V. & Azoulay, E. Molecular targeted therapy-related life- 86. Chow, L. W. C., Lie, E. F. & Toi, M. Advances in EGFR/HER2-directed clinical
threatening toxicity in patients with malignancies. A systematic review of research on breast cancer. Adv. Cancer Res. 147, 375–428 (2020).
published cases. Intensive Care Med. 45, 988–997 (2019). 87. Galizia, G. et al. Cetuximab, a chimeric human mouse anti-epidermal growth
54. Roskoski, R. Jr. The ErbB/HER family of protein-tyrosine kinases and cancer. factor receptor monoclonal antibody, in the treatment of human colorectal
Pharmacol. Res. 79, 34–74 (2014). cancer. Oncogene 26, 3654–3660 (2007).
55. Scaltriti, M. & Baselga, J. The epidermal growth factor receptor pathway: a model 88. Li, Q. H. et al. Anti-EGFR therapy in metastatic colorectal cancer: mechanisms
for targeted therapy. Clin. Cancer Res. 12, 5268–5272 (2006). and potential regimens of drug resistance. Gastroenterol. Rep. 8, 179–191
56. Dean-Colomb, W. & Esteva, F. J. Her2-positive breast cancer: herceptin and (2020).
beyond. Eur. J. Cancer 44, 2806–2812 (2008). 89. Keating, G. M. Panitumumab: a review of its use in metastatic colorectal cancer.
57. Pirker, R. et al. Consensus for EGFR mutation testing in non-small cell lung Drugs 70, 1059–1078 (2010).
cancer: results from a European workshop. J. Thorac. Oncol. 5, 1706–1713 (2010). 90. Nami, B., Maadi, H. & Wang, Z. Mechanisms underlying the action and synergism
58. Thomas, R. & Weihua, Z. Rethink of EGFR in cancer with its kinase independent of trastuzumab and pertuzumab in targeting HER2-positive breast cancer.
function on board. Front. Oncol. 9, 800 (2019). Cancers 10, 342 (2018).
59. Guo, G. et al. Ligand-independent EGFR signaling. Cancer Res. 75, 3436–3441 91. Cho, S. M., Esmail, A., Raza, A., Dacha, S. & Abdelrahim, M. Timeline of FDA-
(2015). approved targeted therapy for cholangiocarcinoma. Cancers 14, 2641 (2022).
60. Wee, P. & Wang, Z. Epidermal growth factor receptor cell proliferation signaling 92. Della Corte, C. M. et al. Role and targeting of anaplastic lymphoma kinase in
pathways. Cancers 9, 52 (2017). cancer. Mol. Cancer 17, 30 (2018).
61. Ha, S. Y. et al. Lung cancer in never-smoker Asian females is driven by oncogenic 93. Webb, T. R. et al. Anaplastic lymphoma kinase: role in cancer pathogenesis and
mutations, most often involving EGFR. Oncotarget 6, 5465–5474 (2015). small-molecule inhibitor development for therapy. Expert Rev. Anticancer Ther. 9,
62. Amelia, T., Kartasasmita, R. E., Ohwada, T. & Tjahjono, D. H. Structural insight and 331–356 (2009).
development of EGFR tyrosine kinase inhibitors. Molecules 27, 819 (2022). 94. Takeuchi, K. et al. Multiplex reverse transcription-PCR screening for EML4-ALK
63. Giaccone, G. The role of gefitinib in lung cancer treatment. Clin. Cancer Res. 10, fusion transcripts. Clin. Cancer Res 14, 6618–6624 (2008).
4233s–4237s (2004). 95. Katayama, R., Lovly, C. M. & Shaw, A. T. Therapeutic targeting of anaplastic
64. Johnson, J. R. et al. Approval summary for erlotinib for treatment of patients lymphoma kinase in lung cancer: a paradigm for precision cancer medicine. Clin.
with locally advanced or metastatic non-small cell lung cancer after failure of at Cancer Res. 21, 2227–2235 (2015).
least one prior chemotherapy regimen. Clin. Cancer Res. 11, 6414–6421 (2005). 96. Golding, B., Luu, A., Jones, R. & Viloria-Petit, A. M. The function and therapeutic
65. Li, D. et al. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in targeting of anaplastic lymphoma kinase (ALK) in non-small cell lung cancer
preclinical lung cancer models. Oncogene 27, 4702–4711 (2008). (NSCLC). Mol. Cancer 17, 52 (2018).
66. Lau, S. C. M., Batra, U., Mok, T. S. K. & Loong, H. H. Dacomitinib in the man- 97. Zou, H. Y. et al. An orally available small-molecule inhibitor of c-Met, PF-
agement of advanced non-small-cell lung cancer. Drugs 79, 823–831 (2019). 2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and
67. Kobayashi, Y. et al. EGFR T790M and C797S mutations as mechanisms of antiangiogenic mechanisms. Cancer Res. 67, 4408–4417 (2007).
acquired resistance to dacomitinib. J. Thorac. Oncol. 13, 727–731 (2018). 98. Shaw, A. T. et al. Crizotinib in ROS1-rearranged advanced non-small-cell lung
68. Sharma, S. V., Bell, D. W., Settleman, J. & Haber, D. A. Epidermal growth factor cancer (NSCLC): updated results, including overall survival, from PROFILE 1001.
receptor mutations in lung cancer. Nat. Rev. Cancer 7, 169–181 (2007). Ann. Oncol. 30, 1121–1126 (2019).
69. Suda, K., Onozato, R., Yatabe, Y. & Mitsudomi, T. EGFR T790M mutation: a double 99. Hong, L., Zhang, J., Heymach, J. V. & Le, X. Current and future treatment options
role in lung cancer cell survival? J. Thorac. Oncol. 4, 1–4 (2009). for MET exon 14 skipping alterations in non-small cell lung cancer. Ther. Adv.
70. Cross, D. A. et al. AZD9291, an irreversible EGFR TKI, overcomes T790M- Med. Oncol. 13, 1758835921992976 (2021).
mediated resistance to EGFR inhibitors in lung cancer. Cancer Disco. 4, 100. Ernani, V. & Stinchcombe, T. E. Management of brain metastases in non–small-
1046–1061 (2014). cell lung cancer. JCO Oncol. Pract. 15, 563–570 (2019).
71. Santarpia, M. et al. Osimertinib in the treatment of non-small-cell lung cancer: 101. Naito, T., Shiraishi, H. & Fujiwara, Y. Brigatinib and lorlatinib: their effect on ALK
design, development and place in therapy. Lung Cancer 8, 109–125 (2017). inhibitors in NSCLC focusing on resistant mutations and central nervous system
72. Dhillon, S. Lazertinib: first approval. Drugs 81, 1107–1113 (2021). metastases. Jpn. J. Clin. Oncol. 51, 37–44 (2021).
73. Shah, R. R. & Shah, D. R. Safety and tolerability of epidermal growth factor 102. Zhang, S. et al. The potent ALK inhibitor Brigatinib (AP26113) overcomes
receptor (EGFR) tyrosine kinase inhibitors in oncology. Drug Saf. 42, 181–198 mechanisms of resistance to first- and second-generation ALK inhibitors in
(2019). preclinical models. Clin. Cancer Res. 22, 5527–5538 (2016).
74. Duggirala, K. B., Lee, Y. & Lee, K. Chronicles of EGFR tyrosine kinase inhibitors: 103. Eder, J. P., Vande Woude, G. F., Boerner, S. A. & LoRusso, P. M. Novel therapeutic
targeting EGFR C797S containing triple mutations. Biomol. Ther. 30, 19–27 inhibitors of the c-Met signaling pathway in cancer. Clin. Cancer Res 15,
(2022). 2207–2214 (2009).
75. Leonetti, A. et al. Resistance mechanisms to osimertinib in EGFR-mutated non- 104. Turke, A. B. et al. Preexistence and clonal selection of MET amplification in EGFR
small cell lung cancer. Br. J. Cancer 121, 725–737 (2019). mutant NSCLC. Cancer Cell 17, 77–88 (2010).
76. Wang, S., Song, Y. & Liu, D. EAI045: The fourth-generation EGFR inhibitor 105. Frampton, G. M. et al. Activation of MET via diverse exon 14 splicing alterations
overcoming T790M and C797S resistance. Cancer Lett. 385, 51–54 (2017). occurs in multiple tumor types and confers clinical sensitivity to MET inhibitors.
77. Schalm, S. S. et al. 1296P BLU-945, a highly potent and selective 4th generation Cancer Disco. 5, 850–859 (2015).
EGFR TKI for the treatment of EGFR T790M/C797S resistant NSCLC. Ann. Oncol. 106. Cocco, E., Scaltriti, M. & Drilon, A. NTRK fusion-positive cancers and TRK inhibitor
31, S839 (2020). therapy. Nat. Rev. Clin. Oncol. 15, 731–747 (2018).
78. Kim, D. S. et al. Abstract 5350: OBX02-011, a reversible fourth-generation EGFR- 107. Laetsch, T. W. & Hong, D. S. Tropomyosin receptor kinase inhibitors for the
TKI, overcomes C797S-mediated resistance in non-small cell lung cancer. Cancer treatment of TRK fusion cancer. Clin. Cancer Res. 27, 4974–4982 (2021).
Res. 82, 5350 (2022). 108. Kazi, J. U. & Ronnstrand, L. FMS-like tyrosine kinase 3/FLT3: from basic science to
79. Rivera-Concepcion, J., Uprety, D. & Adjei, A. A. Challenges in the use of targeted clinical implications. Physiol. Rev. 99, 1433–1466 (2019).
therapies in non-small cell lung cancer. Cancer Res. Treat. 54, 315–329 (2022). 109. Perl, A. E. Availability of FLT3 inhibitors: how do we use them? Blood 134,
80. Kohler, J. & Janne, P. A. Amivantamab: treating EGFR Exon 20-mutant cancers 741–745 (2019).
with bispecific antibody-mediated receptor degradation. J. Clin. Oncol. 39, 110. Kohlmann, A. et al. Gene expression profiling in AML with normal karyotype can
3403–3406 (2021). predict mutations for molecular markers and allows novel insights into per-
81. Pacheco, J. M. Mobocertinib: a potential treatment for NSCLC with EGFR Exon 20 turbed biological pathways. Leukemia 24, 1216–1220 (2010).
insertions. Cancer Disco. 11, 1617–1619 (2021). 111. Crook, T. et al. Angiogenesis inhibitors in personalized combination regimens
82. Rusnak, D. & Gilmer, T. M. The discovery of lapatinib (GW572016). Mol. Cancer for the treatment of advanced refractory cancers. Front. Mol. Med. 1, 749283
Ther. 10, 2019 (2011). (2021).

1692
112. Chen, P. H., Chen, X. & He, X. Platelet-derived growth factors and their recep- 142. Eskazan, A. E. & Keskin, D. Radotinib and its clinical potential in chronic-phase
tors: structural and functional perspectives. Biochim. Biophys. Acta 1834, chronic myeloid leukemia patients: an update. Ther. Adv. Hematol. 8, 237–243
2176–2186 (2013). (2017).
113. Andrae, J., Gallini, R. & Betsholtz, C. Role of platelet-derived growth factors in 143. Schoepfer, J. et al. Discovery of asciminib (ABL001), an allosteric inhibitor of the
physiology and medicine. Genes Dev. 22, 1276–1312 (2008). tyrosine kinase activity of BCR-ABL1. J. Med. Chem. 61, 8120–8135 (2018).
114. Heldin, C. H. Targeting the PDGF signaling pathway in tumor treatment. Cell 144. Hughes, T. P. et al. Asciminib in chronic myeloid leukemia after ABL kinase
Commun. Signal. 11, 97 (2013). inhibitor failure. N. Engl. J. Med. 381, 2315–2326 (2019).
115. Ellis, L. M. & Hicklin, D. J. VEGF-targeted therapy: mechanisms of anti-tumour 145. Tan, F. H., Putoczki, T. L., Stylli, S. S. & Luwor, R. B. Ponatinib: a novel multi-
activity. Nat. Rev. Cancer 8, 579–591 (2008). tyrosine kinase inhibitor against human malignancies. Onco. Targets Ther. 12,
116. Harper, S. J. & Bates, D. O. VEGF-A splicing: the key to anti-angiogenic ther- 635–645 (2019).
apeutics? Nat. Rev. Cancer 8, 880–887 (2008). 146. Parsons, S. J. & Parsons, J. T. Src family kinases, key regulators of signal trans-
117. El-Kenawi, A. E. & El-Remessy, A. B. Angiogenesis inhibitors in cancer therapy: duction. Oncogene 23, 7906–7909 (2004).
mechanistic perspective on classification and treatment rationales. Br. J. Phar- 147. Wheeler, D. L., Iida, M. & Dunn, E. F. The role of Src in solid tumors. Oncologist 14,
macol. 170, 712–729 (2013). 667–678 (2009).
118. Scavelli, C., Vacca, A., Di Pietro, G., Dammacco, F. & Ribatti, D. Crosstalk between 148. Zhang, S. & Yu, D. Targeting Src family kinases in anti-cancer therapies: turning
angiogenesis and lymphangiogenesis in tumor progression. Leukemia 18, promise into triumph. Trends Pharmacol. Sci. 33, 122–128 (2012).
1054–1058 (2004). 149. Das, J. et al. 2-aminothiazole as a novel kinase inhibitor template. Structure-
119. Liang, Y., Brekken, R. A. & Hyder, S. M. Vascular endothelial growth factor activity relationship studies toward the discovery of N-(2-chloro-6-methylphe-
induces proliferation of breast cancer cells and inhibits the anti-proliferative nyl)-2-[[6-[4-(2-hydroxyethyl)-1-piperazinyl)]-2-methyl-4-pyrimidinyl]amino)]-
activity of anti-hormones. Endocr. Relat. Cancer 13, 905–919 (2006). 1,3-thiazole-5-carboxamide (dasatinib, BMS-354825) as a potent pan-Src kinase
120. Kong, D. et al. VEGF-C mediates tumor growth and metastasis through pro- inhibitor. J. Med. Chem. 49, 6819–6832 (2006).
moting EMT-epithelial breast cancer cell crosstalk. Oncogene 40, 964–979 150. Martellucci, S. et al. Src Family Kinases as Therapeutic Targets in Advanced Solid
(2021). Tumors: What We Have Learned so Far. Cancers 12, 1448 (2020).
121. Zhao, D. et al. VEGF drives cancer-initiating stem cells through VEGFR-2/ 151. Wen, T., Wang, J., Shi, Y., Qian, H. & Liu, P. Inhibitors targeting Bruton’s tyrosine
Stat3 signaling to upregulate Myc and Sox2. Oncogene 34, 3107–3119 (2015). kinase in cancers: drug development advances. Leukemia 35, 312–332 (2021).
122. Kaplan, R. N. et al. VEGFR1-positive haematopoietic bone marrow progenitors 152. Pal Singh, S., Dammeijer, F. & Hendriks, R. W. Role of Bruton’s tyrosine kinase in B
initiate the pre-metastatic niche. Nature 438, 820–827 (2005). cells and malignancies. Mol. Cancer 17, 57 (2018).
123. Beenken, A. & Mohammadi, M. The FGF family: biology, pathophysiology and 153. Seavey, M. M. & Dobrzanski, P. The many faces of Janus kinase. Biochem.
therapy. Nat. Rev. Drug Discov. 8, 235–253 (2009). Pharmacol. 83, 1136–1145 (2012).
124. Babina, I. S. & Turner, N. C. Advances and challenges in targeting FGFR signalling 154. Lee, H. J., Daver, N., Kantarjian, H. M., Verstovsek, S. & Ravandi, F. The role of JAK
in cancer. Nat. Rev. Cancer 17, 318–332 (2017). pathway dysregulation in the pathogenesis and treatment of acute myeloid
125. Regeenes, R. et al. Fibroblast growth factor receptor 5 (FGFR5) is a co-receptor leukemia. Clin. Cancer Res. 19, 327–335 (2013).
for FGFR1 that is up-regulated in beta-cells by cytokine-induced inflammation. J. 155. Quintas-Cardama, A. & Verstovsek, S. Molecular pathways: Jak/STAT pathway:
Biol. Chem. 293, 17218–17228 (2018). mutations, inhibitors, and resistance. Clin. Cancer Res. 19, 1933–1940 (2013).
126. Xie, Y. et al. FGF/FGFR signaling in health and disease. Signal Transduct. Target. 156. Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer.
Ther. 5, 181 (2020). Cancer Res. 80, 2969–2974 (2020).
127. Liang, J. et al. The C-kit receptor-mediated signal transduction and tumor- 157. Yaeger, R. & Corcoran, R. B. Targeting alterations in the RAF-MEK pathway.
related diseases. Int. J. Biol. Sci. 9, 435–443 (2013). Cancer Disco. 9, 329–341 (2019).
128. Salvatore, D., Santoro, M. & Schlumberger, M. The importance of the RET gene in 158. Yang, J. et al. Targeting PI3K in cancer: mechanisms and advances in clinical
thyroid cancer and therapeutic implications. Nat. Rev. Endocrinol. 17, 296–306 trials. Mol. Cancer 18, 26 (2019).
(2021). 159. Lim, S. & Kaldis, P. Cdks, cyclins and CKIs: roles beyond cell cycle regulation.
129. Jones, N., Iljin, K., Dumont, D. J. & Alitalo, K. Tie receptors: new modulators of Development 140, 3079–3093 (2013).
angiogenic and lymphangiogenic responses. Nat. Rev. Mol. Cell. Biol. 2, 257–267 160. Otto, T. & Sicinski, P. Cell cycle proteins as promising targets in cancer therapy.
(2001). Nat. Rev. Cancer 17, 93–115 (2017).
130. Hume, D. A. & MacDonald, K. P. Therapeutic applications of macrophage colony- 161. Cho, K. N. & Lee, K. I. Chemistry and biology of Ras farnesyltransferase. Arch.
stimulating factor-1 (CSF-1) and antagonists of CSF-1 receptor (CSF-1R) signal- Pharm. Res. 25, 759–769 (2002).
ing. Blood 119, 1810–1820 (2012). 162. Wang, J., Yao, X. & Huang, J. New tricks for human farnesyltransferase inhibitor:
131. Soares, M. J. et al. CSF1R copy number changes, point mutations, and RNA cancer and beyond. Medchemcomm 8, 841–854 (2017).
and protein overexpression in renal cell carcinomas. Mod. Pathol. 22, 744–752 163. Zhang, S. S. & Nagasaka, M. Spotlight on Sotorasib (AMG 510) for KRAS (G12C)
(2009). positive non-small cell lung cancer. Lung Cancer 12, 115–122 (2021).
132. Yang, X. H., Hand, R. A., Livasy, C. A., Cance, W. G. & Craven, R. J. Overexpression 164. Blair, H. A. Sotorasib: first approval. Drugs 81, 1573–1579 (2021).
of the receptor tyrosine kinase Tie-1 intracellular domain in breast cancer. 165. Janne, P. A. et al. Adagrasib in non-small-cell lung cancer harboring a
Tumor Biol. 24, 61–69 (2003). KRAS(G12C) mutation. N. Engl. J. Med. 387, 120–131 (2022).
133. Roskoski, R. Jr. The role of fibroblast growth factor receptor (FGFR) protein- 166. Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage.
tyrosine kinase inhibitors in the treatment of cancers including those of the Nat. Rev. Mol. Cell. Biol. 5, 875–885 (2004).
urinary bladder. Pharmacol. Res. 151, 104567 (2020). 167. Yuan, J., Dong, X., Yap, J. & Hu, J. The MAPK and AMPK signalings: interplay and
134. Yamaoka, T., Kusumoto, S., Ando, K., Ohba, M. & Ohmori, T. Receptor tyrosine implication in targeted cancer therapy. J. Hematol. Oncol. 13, 113 (2020).
kinase-targeted cancer therapy. Int. J. Mol. Sci. 19, 3491 (2018). 168. Koelblinger, P., Thuerigen, O. & Dummer, R. Development of encorafenib for
135. Greuber, E. K., Smith-Pearson, P., Wang, J. & Pendergast, A. M. Role of ABL family BRAF-mutated advanced melanoma. Curr. Opin. Oncol. 30, 125–133 (2018).
kinases in cancer: from leukaemia to solid tumours. Nat. Rev. Cancer 13, 559–571 169. Saxton, R. A. & Sabatini, D. M. mTOR signaling in growth, metabolism, and
(2013). disease. Cell 168, 960–976 (2017).
136. Colicelli, J. ABL tyrosine kinases: evolution of function, regulation, and specifi- 170. Liu, R. et al. PI3K/AKT pathway as a key link modulates the multidrug resistance
city. Sci. Signal. 3, re6 (2010). of cancers. Cell Death Dis. 11, 797 (2020).
137. Rossari, F., Minutolo, F. & Orciuolo, E. Past, present, and future of Bcr-Abl inhi- 171. Chauhan, A. F. & Cheson, B. D. Copanlisib in the treatment of relapsed follicular
bitors: from chemical development to clinical efficacy. J. Hematol. Oncol. 11, 84 lymphoma: utility and experience from the clinic. Cancer Manag. Res. 13,
(2018). 677–692 (2021).
138. Giles, F. J., O’Dwyer, M. & Swords, R. Class effects of tyrosine kinase inhibitors in 172. Cheah, C. Y. & Fowler, N. H. Idelalisib in the management of lymphoma. Blood
the treatment of chronic myeloid leukemia. Leukemia 23, 1698–1707 (2009). 128, 331–336 (2016).
139. Weisberg, E. et al. AMN107 (nilotinib): a novel and selective inhibitor of BCR-ABL. 173. Lu, J. Palbociclib: a first-in-class CDK4/CDK6 inhibitor for the treatment of
Br. J. Cancer 94, 1765–1769 (2006). hormone-receptor positive advanced breast cancer. J. Hematol. Oncol. 8, 98 (2015).
140. Puttini, M. et al. In vitro and in vivo activity of SKI-606, a novel Src-Abl inhi- 174. Hortobagyi, G. N. Ribociclib for the first-line treatment of advanced hormone
bitor, against imatinib-resistant Bcr-Abl+ neoplastic cells. Cancer Res. 66, receptor-positive breast cancer: a review of subgroup analyses from the
11314–11322 (2006). MONALEESA-2 trial. Breast Cancer Res 20, 123 (2018).
141. Hochhaus, A. et al. Chronic myeloid leukaemia: ESMO Clinical Practice Guide- 175. Lord, C. J. & Ashworth, A. PARP inhibitors: Synthetic lethality in the clinic. Science
lines for diagnosis, treatment and follow-up. Ann. Oncol. 28, iv41–iv51 (2017). 355, 1152–1158 (2017).

1693
176. Pilie, P. G., Gay, C. M., Byers, L. A., O’Connor, M. J. & Yap, T. A. PARP inhibitors: 208. Zhao, B. et al. Mechanisms of resistance to anti-EGFR therapy in colorectal
extending benefit beyond BRCA-mutant cancers. Clin. Cancer Res. 25, cancer. Oncotarget 8, 3980–4000 (2017).
3759–3771 (2019). 209. Boekhout, A. H., Beijnen, J. H. & Schellens, J. H. Trastuzumab. Oncologist 16,
177. Lord, C. J. & Ashworth, A. BRCAness revisited. Nat. Rev. Cancer 16, 110–120 800–810 (2011).
(2016). 210. Howie, L. J. et al. FDA approval summary: pertuzumab for adjuvant treatment of
178. Rose, M., Burgess, J. T., O’Byrne, K., Richard, D. J. & Bolderson, E. PARP inhibitors: HER2-positive early breast cancer. Clin. Cancer Res. 25, 2949–2955 (2019).
clinical relevance, mechanisms of action and tumor resistance. Front. Cell Dev. 211. Schlam, I. & Swain, S. M. HER2-positive breast cancer and tyrosine kinase inhi-
Biol. 8, 564601 (2020). bitors: the time is now. NPJ Breast Cancer 7, 56 (2021).
179. Meng, F., Liang, Z., Zhao, K. & Luo, C. Drug design targeting active post- 212. Sudhan, D. R. et al. Hyperactivation of TORC1 drives resistance to the Pan-HER
translational modification protein isoforms. Med. Res. Rev. 41, 1701–1750 (2021). tyrosine kinase inhibitor neratinib in HER2-mutant cancers. Cancer Cell 37,
180. Bekes, M., Langley, D. R. & Crews, C. M. PROTAC targeted protein degraders: the 183–199 (2020).
past is prologue. Nat. Rev. Drug Discov. 21, 181–200 (2022). 213. Recondo, G., Facchinetti, F., Olaussen, K. A., Besse, B. & Friboulet, L. Making the
181. Moore, A. R., Rosenberg, S. C., McCormick, F. & Malek, S. RAS-targeted therapies: first move in EGFR-driven or ALK-driven NSCLC: first-generation or next-
is the undruggable drugged? Nat. Rev. Drug Discov. 19, 533–552 (2020). generation TKI? Nat. Rev. Clin. Oncol. 15, 694–708 (2018).
182. Ostrem, J. M., Peters, U., Sos, M. L., Wells, J. A. & Shokat, K. M. K-Ras(G12C) 214. Fujino, T. et al. Foretinib can overcome common on-target resistance mutations
inhibitors allosterically control GTP affinity and effector interactions. Nature 503, after capmatinib/tepotinib treatment in NSCLCs with MET exon 14 skipping
548–551 (2013). mutation. J. Hematol. Oncol. 15, 79 (2022).
183. Lietman, C. D., Johnson, M. L., McCormick, F. & Lindsay, C. R. More to the RAS 215. Cerchione, C. et al. Safety of FLT3 inhibitors in patients with acute myeloid
story: KRAS(G12C) inhibition, resistance mechanisms, and moving beyond leukemia. Expert Rev. Hematol. 14, 851–865 (2021).
KRAS(G12C). Am. Soc. Clin. Oncol. Educ. Book 42, 1–13 (2022). 216. Desikan, S. P. et al. Resistance to targeted therapies: delving into FLT3 and IDH.
184. Lim, S. M. et al. Therapeutic targeting of oncogenic K-Ras by a covalent catalytic Blood Cancer J. 12, 91 (2022).
site inhibitor. Angew. Chem. Int. Ed. Engl. 53, 199–204 (2014). 217. Friedman, R. The molecular mechanisms behind activation of FLT3 in acute
185. Wang, X. et al. Identification of MRTX1133, a noncovalent, potent, and selective myeloid leukemia and resistance to therapy by selective inhibitors. Biochim.
KRAS(G12D) inhibitor. J. Med. Chem. 65, 3123–3133 (2022). Biophys. Acta Rev. Cancer 1877, 188666 (2022).
186. Mao, Z. et al. KRAS(G12D) can be targeted by potent inhibitors via formation of 218. Goodman, V. L. et al. Approval summary: sunitinib for the treatment of imatinib
salt bridge. Cell Disco. 8, 5 (2022). refractory or intolerant gastrointestinal stromal tumors and advanced renal cell
187. McCutcheon, J. N. & Giaccone, G. Next-generation sequencing: targeting tar- carcinoma. Clin. Cancer Res. 13, 1367–1373 (2007).
geted therapies. Clin. Cancer Res. 21, 3584–3585 (2015). 219. Joosten, S. C. et al. Resistance to sunitinib in renal cell carcinoma: from mole-
188. Udagawa, C. & Zembutsu, H. Pharmacogenetics for severe adverse drug reac- cular mechanisms to predictive markers and future perspectives. Biochim. Bio-
tions induced by molecular-targeted therapy. Cancer Sci. 111, 3445–3457 (2020). phys. Acta 1855, 1–16 (2015).
189. Keshava, N. et al. Defining subpopulations of differential drug response to reveal 220. Qin, S. et al. Recent advances on anti-angiogenesis receptor tyrosine kinase
novel target populations. NPJ Syst. Biol. Appl. 5, 36 (2019). inhibitors in cancer therapy. J. Hematol. Oncol. 12, 27 (2019).
190. Luo, Y., Peng, J. & Ma, J. Next Decade’s AI-based drug development features 221. Fallahi, P. et al. Selective use of vandetanib in the treatment of thyroid cancer.
tight integration of data and computation. Health Data Sci. 2022, 9816939 Drug Des. Devel. Ther. 9, 3459–3470 (2015).
(2022). 222. Bauer, S., George, S., von Mehren, M. & Heinrich, M. C. Early and next-generation
191. Ting, N. L., Lau, H. C. & Yu, J. Cancer pharmacomicrobiomics: targeting micro- KIT/PDGFRA kinase inhibitors and the future of treatment for advanced gas-
biota to optimise cancer therapy outcomes. Gut 71, 1412–1425 (2022). trointestinal stromal tumor. Front. Oncol. 11, 672500 (2021).
192. Ramirez-Labrada, A. G. et al. The influence of lung microbiota on lung carci- 223. Cowey, C. L. Profile of tivozanib and its potential for the treatment of advanced
nogenesis, immunity, and immunotherapy. Trends Cancer 6, 86–97 (2020). renal cell carcinoma. Drug Des. Devel. Ther. 7, 519–527 (2013).
193. Kadosh, E. et al. The gut microbiome switches mutant p53 from tumour- 224. Kommalapati, A., Tella, S. H., Borad, M., Javle, M. & Mahipal, A. FGFR inhibitors in
suppressive to oncogenic. Nature 586, 133–138 (2020). oncology: insight on the management of toxicities in clinical practice. Cancers
194. Gopalakrishnan, V. et al. Gut microbiome modulates response to anti-PD-1 13, 2968 (2021).
immunotherapy in melanoma patients. Science 359, 97–103 (2018). 225. Yue, S. et al. FGFR-TKI resistance in cancer: current status and perspectives. J.
195. Nagano, T., Tachihara, M. & Nishimura, Y. Mechanism of resistance to epidermal Hematol., Oncol. 14, 23 (2021).
growth factor receptor-tyrosine kinase inhibitors and a potential treatment 226. Jiang, K. et al. GZD824 overcomes FGFR1-V561F/M mutant resistance in vitro
strategy. Cells 7, 212 (2018). and in vivo. Cancer Med 10, 4874–4884 (2021).
196. van der Wekken, A. J. et al. Resistance mechanisms after tyrosine kinase inhi- 227. Thein, K. Z., Velcheti, V., Mooers, B. H. M., Wu, J. & Subbiah, V. Precision therapy
bitors afatinib and crizotinib in non-small cell lung cancer, a review of the for RET-altered cancers with RET inhibitors. Trends Cancer 7, 1074–1088 (2021).
literature. Crit. Rev. Oncol. Hematol. 100, 107–116 (2016). 228. Lin, J. J. & Gainor, J. F. An early look at selective RET inhibitor resistance: new
197. Sequist, L. V. et al. Genotypic and histological evolution of lung cancers challenges and opportunities. Br. J. Cancer 124, 1757–1758 (2021).
acquiring resistance to EGFR inhibitors. Sci. Transl. Med. 3, 75ra26 (2011). 229. Garcia, J. et al. Bevacizumab (Avastin(R)) in cancer treatment: a review of 15
198. Dungo, R. T. & Keating, G. M. Afatinib: first global approval. Drugs 73, 1503–1515 years of clinical experience and future outlook. Cancer Treat. Rev. 86, 102017
(2013). (2020).
199. Zhang, Y. et al. The efficacy and toxicity of afatinib in advanced EGFR-positive 230. Young, K., Smyth, E. & Chau, I. Ramucirumab for advanced gastric cancer or
non-small-cell lung cancer patients after failure of first-generation tyrosine gastro-oesophageal junction adenocarcinoma. Ther. Adv. Gastroenterol. 8,
kinase inhibitors: a systematic review and meta-analysis. J. Thorac. Dis. 9, 373–383 (2015).
1980–1987 (2017). 231. Ha, D., Choi, S. R., Kwon, Y., Park, H. H. & Shin, J. Y. Pattern of adverse events
200. Shirley, M. Dacomitinib: first global approval. Drugs 78, 1947–1953 (2018). induced by aflibercept and ranibizumab: a nationwide spontaneous adverse
201. Reungwetwattana, T., Rohatgi, N., Mok, T. S. & Prabhash, K. Dacomitinib as first- event reporting database, 2007–2016. Medicine 98, e16785 (2019).
line treatment for EGFR mutation-positive non-small cell lung cancer. Expert Rev. 232. Braun, T. P., Eide, C. A. & Druker, B. J. Response and resistance to BCR-ABL1-
Precis. Med. Drug Dev. 6, 161–171 (2021). targeted therapies. Cancer Cell 37, 530–542 (2020).
202. Greig, S. L. Osimertinib: first global approval. Drugs 76, 263–273 (2016). 233. Conchon, M., Freitas, C. M., Rego, M. A. & Braga Junior, J. W. Dasatinib - clinical
203. Cooper, A. J., Sequist, L. V. & Lin, J. J. Third-generation EGFR and ALK inhibitors: trials and management of adverse events in imatinib resistant/intolerant
mechanisms of resistance and management. Nat. Rev. Clin. Oncol. 19, 499–514 chronic myeloid leukemia. Rev. Bras. Hematol. Hemoter. 33, 131–139 (2011).
(2022). 234. Kim, S. H. et al. Efficacy and safety of radotinib in chronic phase chronic myeloid
204. Vogel, W. H. & Jennifer, P. Management strategies for adverse events associated leukemia patients with resistance or intolerance to BCR-ABL1 tyrosine kinase
with EGFR TKIs in non-small cell lung cancer. J. Adv. Pract. Oncol. 7, 723–735 inhibitors. Haematologica 99, 1191–1196 (2014).
(2016). 235. Lipsky, A. & Lamanna, N. Managing toxicities of Bruton tyrosine kinase inhibitors.
205. Cetuximab approved by FDA for treatment of head and neck squamous cell Hematol. Am. Soc. Hematol. Educ. Program 2020, 336–345 (2020).
cancer. Cancer Biol. Ther. 5, 340–342 (2006). 236. Estupinan, H. Y. et al. BTK gatekeeper residue variation combined with cysteine
206. Peeters, M., Karthaus, M., Rivera, F., Terwey, J. H. & Douillard, J. Y. Panitumumab 481 substitution causes super-resistance to irreversible inhibitors acalabrutinib,
in metastatic colorectal cancer: the importance of tumour RAS status. Drugs 75, ibrutinib and zanubrutinib. Leukemia 35, 1317–1329 (2021).
731–748 (2015). 237. Talpaz, M. & Kiladjian, J. J. Fedratinib, a newly approved treatment for patients
207. Thomas, M. Cetuximab: adverse event profile and recommendations for toxicity with myeloproliferative neoplasm-associated myelofibrosis. Leukemia 35, 1–17
management. Clin. J. Oncol. Nurs. 9, 332–338 (2005). (2021).

1694
238. Zhao, Y. et al. Diverse alterations associated with resistance to KRAS(G12C) 256. Yue, X., Chen, Q. & He, J. Combination strategies to overcome resistance to the
inhibition. Nature 599, 679–683 (2021). BCL2 inhibitor venetoclax in hematologic malignancies. Cancer Cell Int. 20, 524
239. Proietti, I. et al. Mechanisms of acquired BRAF inhibitor resistance in melanoma: (2020).
a systematic review. Cancers 12, 2801 (2020). 257. Xie, H., Paradise, B. D., Ma, W. W. & Fernandez-Zapico, M. E. Recent advances in
240. Sanchez, J. N., Wang, T. & Cohen, M. S. BRAF and MEK inhibitors: use and the clinical targeting of hedgehog/GLI signaling in cancer. Cells 8, 394 (2019).
resistance in BRAF-mutated cancers. Drugs 78, 549–566 (2018).
241. Welsh, S. J. & Corrie, P. G. Management of BRAF and MEK inhibitor toxicities
in patients with metastatic melanoma. Ther. Adv. Med. Oncol. 7, 122–136 ACKNOWLEDGEMENTS
(2015). This research was supported by a grant from the National Research Foundation of
242. Kun, E., Tsang, Y. T. M., Ng, C. W., Gershenson, D. M. & Wong, K. K. MEK inhibitor Korea (NRF), the Ministry of Science and ICT (MSIT), Republic of Korea (No. NRF-
resistance mechanisms and recent developments in combination trials. Cancer 2016R1A3B1908631).
Treat. Rev. 92, 102137 (2021).
243. Armaghani, A. J. & Han, H. S. Alpelisib in the treatment of breast cancer: a short
review on the emerging clinical data. Breast Cancer 12, 251–258 (2020).
244. Wright, S. C. E., Vasilevski, N., Serra, V., Rodon, J. & Eichhorn, P. J. A. Mechanisms COMPETING INTERESTS
of resistance to PI3K inhibitors in cancer: adaptive responses, drug tolerance The authors declare no competing interests.
and cellular plasticity. Cancers 13, 1538 (2021).
245. Li, Z. et al. Mechanisms of CDK4/6 inhibitor resistance in luminal breast cancer.
Front. Pharmacol. 11, 580251 (2020). ADDITIONAL INFORMATION
246. Royce, M. et al. FDA approval summary: abemaciclib with endocrine therapy for Correspondence and requests for materials should be addressed to Ho-Young Lee.
high-risk early breast cancer. J. Clin. Oncol. 40, 1155–1162 (2022).
247. Awad, M. M. et al. Acquired resistance to KRAS(G12C) inhibition in cancer. N. Reprints and permission information is available at http://www.nature.com/
Engl. J. Med. 384, 2382–2393 (2021). reprints
248. Kaminskas, E., Farrell, A. T., Wang, Y. C., Sridhara, R. & Pazdur, R. FDA drug
approval summary: azacitidine (5-azacytidine, Vidaza) for injectable suspension. Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims
Oncologist 10, 176–182 (2005). in published maps and institutional affiliations.
249. Kim, N. et al. FDA approval summary: decitabine and cedazuridine tablets for
myelodysplastic syndromes. Clin. Cancer Res. 28, 3411–3416 (2022).
250. Bondarev, A. D. et al. Recent developments of HDAC inhibitors: emerging
indications and novel molecules. Br. J. Clin. Pharmacol. 87, 4577–4597 (2021). Open Access This article is licensed under a Creative Commons
251. Fantin, V. R. & Richon, V. M. Mechanisms of resistance to histone deacetylase Attribution 4.0 International License, which permits use, sharing,
inhibitors and their therapeutic implications. Clin. Cancer Res. 13, 7237–7242 adaptation, distribution and reproduction in any medium or format, as long as you give
(2007). appropriate credit to the original author(s) and the source, provide a link to the Creative
252. Julia, E. & Salles, G. EZH2 inhibition by tazemetostat: mechanisms of action, Commons license, and indicate if changes were made. The images or other third party
safety and efficacy in relapsed/refractory follicular lymphoma. Future Oncol. 17, material in this article are included in the article’s Creative Commons license, unless
2127–2140 (2021). indicated otherwise in a credit line to the material. If material is not included in the
253. McMurry, H., Fletcher, L. & Traer, E. IDH inhibitors in AML-promise and pitfalls. article’s Creative Commons license and your intended use is not permitted by statutory
Curr. Hematol. Malig. Rep. 16, 207–217 (2021). regulation or exceeds the permitted use, you will need to obtain permission directly
254. Merin, N. M. & Kelly, K. R. Clinical use of proteasome inhibitors in the treatment from the copyright holder. To view a copy of this license, visit http://
of multiple myeloma. Pharmaceuticals 8, 1–20 (2014). creativecommons.org/licenses/by/4.0/.
255. Bennett, M. K., Pitson, S. M. & Wallington-Beddoe, C. T. In Resistance to Targeted
Therapies in Multiple Myeloma (eds S. C. W. Ling & S. Trieu) 39–59 (Springer
International Publishing, 2021). © The Author(s) 2022

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Molecular targeted therapy for anticancer treatment

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Experimental & Molecular Medicine (2022) 54:1670–1694; https://doi.org/10.1038/s12276-022-00864-3

Received: 10 March 2022 Revised: 18 July 2022 Accepted: 25 July 2022

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Table 1. Classes of selected kinase inhibitors26,28.

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Experimental & Molecular Medicine (2022) 54:1670 – 1694

I1151T/N/S, 1174 C/L/V, bradycardia, liver

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Experimental & Molecular Medicine (2022) 54:1670 – 1694

FGFR1 Novartis) treated with Stromal cell myelosuppression

Experimental & Molecular Medicine (2022) 54:1670 – 1694

and hypertension is a common side effect of bevacizumab and

observed in patients receiving molecular targeted therapy, such

therapy53. The side effects and toxicity of each molecular

targeted therapy are summarized in Tables 2–6.

SMKIs and mAbs in targeted cancer therapy

inhibitors are brieﬂy introduced below.

Receptor tyrosine kinase inhibitors

comprises four members of the ErbB lineage of proteins (ErbB1/

overexpression56. EGFR kinase-activating mutations [e.g., exon 19

Metastatic RET fusion-positive

EGFR mutations, including E884K, D761Y, T854A, and exon 20

insertion, have been detected in NSCLC and found to confer

and are clinically used for treatment of patients with NSCLC

harboring kinase-activating mutations (Table 2). Geﬁtinib and

tion in exon 2068 is associated with acquired resistance to these

ﬁrst- and second-generation EGFR-TKIs67,69 (e.g., approximately

half of NSCLC patients acquire resistance to ﬁrst-generation EGFR-

TKIs69). EGFR T790M provides advantages for the growth and

survival of cancer cells69 and limits the therapeutic efﬁcacy of

EGFR TKIs through both steric hindrance and potentiated ATP

HCC: hepatocellular carcinoma.

binding62,69. Accordingly, EGFR TKIs targeting the T790M mutation

AML: acute myeloid leukemia.

ILD: interstitial lung disease.

have been developed and clinically utilized. Osimertinib, a third-

RCC: renal cell carcinoma.

generation EGFR TKI, inhibits EGFR kinase activity by forming a

covalent bond with the cysteine-797 residue in the ATP-binding

pocket and shows an approximately 200 times greater inhibitory

EGFR TKI, lazertinib, is an orally available, CNS-penetrable, and

irreversible EGFR TKI that inhibits EGFR T790M and kinase-

activating mutations72. Despite the approval of these agents for

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Recombinant Aﬂibercept Zaltrap, Eylea Eylea: Wet age-related Endophthalmitis,

Experimental & Molecular Medicine (2022) 54:1670 – 1694

Experimental & Molecular Medicine (2022) 54:1670 – 1694

an allosteric inhibitor that binds to the myristate pocket of BCR-

ABL and is effective against T315I-mutant BCR-ABL143,144. Ponati-

wild-type and T315I-mutant BCR-ABL135,137,145, also displays

inhibitory effects on the activity of multiple kinases, including

targeting inhibitors have been developed and evaluated pre-

clinically and clinically137.