PERSPECTIVE

published: 16 April 2019

doi: 10.3389/fonc.2019.00263

Identification of Genetic Mutations in

Cancer: Challenge and Opportunity
in the New Era of Targeted Therapy
Jing Jin 1† , Xu Wu 2,3† , Jianhua Yin 2,3 , Mingxing Li 2,3 , Jing Shen 2,3 , Jing Li 4 , Yueshui Zhao 2,3 ,
Qijie Zhao 2,3 , Jingbo Wu 1 , Qinglian Wen 1 , Chi Hin Cho 2,3 , Tao Yi 5*, Zhangang Xiao 2* and
Liping Qu 6
1
Department of Oncology, The Affiliated Hospital of Southwest Medical University, Southwest Medical University, Luzhou,
China, 2 Laboratory of Molecular Pharmacology, Department of Pharmacology, School of Pharmacy, Southwest Medical
University, Luzhou, China, 3 South Sichuan Institute of Translational Medicine, Luzhou, China, 4 Department of Oncology and
Hematology, Hospital (T.C.M) Affiliated to Southwest Medical University, Luzhou, China, 5 School of Chinese Medicine, Hong
Kong Baptist University, Hong Kong, China, 6 College of Pharmacy, Chengdu University of Traditional Chinese Medicine,
Edited by: Chengdu, China
Yan-yan Yan,
Shanxi Datong University, China
The introduction of targeted therapy is the biggest success in the treatment of
Reviewed by:
Shengpeng Wang, cancer in the past few decades. However, heterogeneous cancer is characterized
University of Macau, China by diverse molecular alterations as well as multiple clinical profiles. Specific genetic
Maria Munoz Caffarel,
Biodonostia Health Research Institute,
mutations in cancer therapy targets may increase drug sensitivity, or more frequently
Spain result in therapeutic resistance. In the past 3 years, several novel targeted therapies
Tinghong Ye,
have been approved for cancer treatment, including drugs with new targets (i.e.,
Sichuan University, China
anti-PD1/PDL1 therapies and CDK4/6 inhibitors), mutation targeting drugs (i.e., the
*Correspondence:
Tao Yi EGFR T790M targeting osimertinib), drugs with multiple targets (i.e., the EGFR/HER2
[email protected] dual inhibitor neratinib) and drug combinations (i.e., encorafenib/binimetinib and
Zhangang Xiao
[email protected]
dabrafenib/trametinib). In this perspective, we focus on the most up-to-date knowledge
of targeted therapy and describe how genetic mutations influence the sensitivity of
† These authors have contributed
equally to the work
targeted therapy, highlighting the challenges faced within this era of precision medicine.
Moreover, the strategies that deal with mutation-driven resistance are further discussed.
Specialty section: Advances in these areas would allow for more targeted and effective therapeutic options
This article was submitted to
Cancer Molecular Targets and
for cancer patients.
Therapeutics, Keywords: targeted therapy, cyclin-dependent kinases 4/6, somatic mutation, resistance, EGFR, PD-1/PD-L1
a section of the journal
Frontiers in Oncology

Received: 25 January 2019 INTRODUCTION

Accepted: 22 March 2019
Published: 16 April 2019 Targeted therapies usually present with high selectivity, target precisely to specific gene
Citation: or protein, and exert a biological function with minimal side effects (1), which has
Jin J, Wu X, Yin J, Li M, Shen J, Li J, distinguished them from most conventional non-specific chemotherapeutic drugs. Targeted
Zhao Y, Zhao Q, Wu J, Wen Q, therapy has thus been regarded as the biggest success in the treatment of cancer in the
Cho CH, Yi T, Xiao Z and Qu L (2019)
past few decades. Many novel promising agents have been experimentally designed and
Identification of Genetic Mutations in
Cancer: Challenge and Opportunity in
developed and are increasingly entering clinical evaluation. However, the frequently observed
the New Era of Targeted Therapy. alterations in the drug targets have posed a big challenge to successful cancer treatment.
Front. Oncol. 9:263. Genetic mutations in cancer are resulted from both inherited and environmental factors.
doi: 10.3389/fonc.2019.00263 In a recent report, it is demonstrated that a large proportion of cancer-related mutations

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Jin et al. Cancer Mutations and Targeted Therapy

are due to randomized DNA replication errors (2). Notably, Anti-PD1/PDL1 Therapies
the mutations in cancer therapy targets can greatly affect drug So far, there are a total of 6 anti-PD1/PDL1 therapies that have
sensitivity. Mutation-driven drug resistance is very common in been approved by the FDA. Notably, in 2017, a PD1 antibody
cancer. The efficacy of targeted therapy is thus largely dependent pembrolizumab was approved for the treatment of any solid
on the mutation profile of tumors in patients. Accurate molecular tumor with a mismatch repair deficiency or a microsatellite
and genetic profiling of tumor cells is becoming a routine practice instability. Monotherapy of PD1/PDL1 blockade has received
before the introduction of targeted therapy in patients. great success in many types of cancers (21, 22). However, there
In recent years, great progress has been made in targeted are certain patients that are gradually developing resistance
therapy discovery. Notably, many new drugs are designed after an initial response (23). Mutation-driven resistance of
primarily based on specific genetic background. For instance, anti-PD1/PDL1 therapies has recently been studied in a small
nearly 40–50% of metastatic cutaneous melanoma possess number of cancer patients. Zaretsky et al. reported that
v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutations of JAK1/JAK2 led to the desensitization of cancer
mutations (3), and ∼90% of these BRAF mutations are caused cells to IFN-γ and contributed to an acquired resistance of
by substitution of glutamic acid for valine at codon 600 pembrolizumab in patients with melanoma (23). Moreover, in
(V600E) (4). Two selective BRAF inhibitors vemurafenib and one resistant patient, a frame-shift deletion in exon 1 of the
dabrafenib were approved for the treatment of patients with β-2-microglobulin was detected, which may result in the loss
BRAF-V600E mutation, showing improved progression-free of expression of surface the MHC class I (23). More studies
survival (5). In November 2018, the U.S. Food and Drug are advocated to explore the acquired resistance of immune
Administration (FDA) approved an inhibitor of tropomyosin checkpoint inhibitors.
receptor kinases (TRKs), larotrectinib, for treatment of any type
of solid tumors with TRK gene fusion (6). This is the second Resistance of CDK4/6 Inhibitors
targeted therapy approved not for specific cancer types but Currently, three CDK 4/6 selective targeting inhibitors,
for any cancers with specific mutations. Targeted therapies are palbociclib, ribociclib, and abemaciclib have been approved
becoming more precise. to treat breast cancer. CDK4/6 inhibitors are increasingly
In this perspective, we focus on the updated knowledge of used in clinical settings, but patients eventually show disease
targeted therapy in the last 3 years and describe how genetic progression and the major reasons remain unclear (24).
mutations influence sensitivity of targeted therapy, highlighting Dysregulation of cyclin D1-CDK4/6-retinoblastoma (Rb)
the challenges faced within this era of precision medicine. pathway has been implicated in hormone receptor positive
Moreover, the strategies dealing with mutation-driven resistance (HR+ ) breast cancer and in chemotherapeutic drug-resistance.
are further discussed. Rb is usually intact in HR+ breast cancer and is important
for the efficacy of CDK4/6-inhibitors in the treatment of
breast cancer (25). It is indicated that T47D cells that become
INFLUENCE OF GENETIC MUTATION ON resistant to CDK4/6 inhibitors, develop CCNE1 amplification
SENSITIVITY OF TARGETED THERAPY or Rb1 loss (26). Moreover, the acquisition of multiple de novo
somatic Rb1 mutations in metastatic breast cancer patients
It is well-acknowledged that mutations in therapeutic targets may result in the emergence of a resistance to CDK 4/6
can increase or decrease drug sensitivity (Table 1). The main inhibitors (24). Until now, there has been no report on CDK4/6
challenge of targeted therapy today is the identification of mutations in cancer patients and their effect on efficacy of
particular cancer mutations which affect efficacy of targeted CDK4/6 inhibitors.
therapies as well as the identification of a specific group of
patients most likely or unlikely to respond to certain targeted
therapies. Despite the great challenges, in the last 3 years, we have EGFR and Different Generation of Tyrosine
seen significant progress in targeted therapy (Table 2), largely Kinase Inhibitors (TKIs)
owing to the rise of large-scale sequencing technology and big EGFR is a prevalent target in several human cancers, such as
data analysis. Several novel targets, including the programmed lung, breast, colorectal, thyroid, and melanoma cancer. In lung
death-1/programmed death-ligand 1 (PD1/PDL1) and cyclin- cancer, several generations of small-molecular inhibitors have
dependent kinases 4 and 6 (CDK4/6), have been validated, been developed to target the EGFR tyrosine kinases (27), such
with several new targeted drugs being approved. Some newly as inhibitors gefitinib, erlotinib, osimertinib, and necitumumab.
approved drugs are directly designed to deal with some known The EGFR mutation in non-small cell lung cancer (NSCLC) was
activating mutations, such as the T790M mutation in epidermal first identified in 2004, and the major missense and deletion
growth factor receptor (EGFR). Moreover, many new findings mutation of EGFR in NSCLC occurs in the tyrosine kinase-
have been added to our knowledge of how mutations influence coding domain in exons 18–21 (28). The L858R mutation
targeted therapies [e.g., the inhibitors of human epidermal in the exon 21 and exon-19 frame deletion are the most
growth factor receptor 2 (HER2) and anaplastic lymphoma commonly detected mutation types of EGFR, representing 50
kinase (ALK)]. Here, based on the most updated research in and 40% of tumor patients, respectively (7). These two types of
the last 3 years, we summarize the recent advances of several mutations are sensitive to EGFR tyrosine kinase inhibitors (TKIs)
targeted therapies. in NSCLC. The first-generation TKIs, gefitinib and erlotinib,

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Jin et al. Cancer Mutations and Targeted Therapy

TABLE 1 | Therapeutic response of targeted therapy in mutant cancers.

Drugs Sensitivity Target mutations Cancer types Reference

Gefitinib + EGFR-L858R Lung cancer (7)

Erlotinib + EGFR-L858R Lung cancer (7)
Gefitinib – EGFR-T789M Lung cancer (8)
Osimertinib + EGFR-T790M Lung cancer (9)
Osimertinib – EGFR-L718Q Lung cancer (10)
Trastuzumab – HER2-A859T, -G776L Lung cancer (11)
Afatinib + HER2-p.Tyr772_Ala775dup Lung cancer (12)
Neratinib – HER2-T798I, -L869R Breast cancer (13)
Lapatinib – HER2-T798M Breast cancer (14)
Trastuzumab – HER2-T798M Breast cancer (14)
Neratinib + HER2-S310, -L755, -V777, -G778_P780dup, and -Y772_A775dup Breast, cervical and biliary cancers (15)
Crizotinib – ALK-C1156Y, -L1196M Lung cancer (16, 17)
Lorlatinib – ALK-L1198F Lung cancer (18)
2,4-Pyrimidinediamine derivative – EML4-ALK-C1156Y, -L1196M Lung cancer (19)
TAE684 – EML4-ALK-L1152R Lung cancer (20)
Dabrafenib + BRAF-V600E Melanoma (5)

TABLE 2 | Cancer targeted therapy approved by FDA in 2017 and 2018.

Drugs Targets Cancer types

Pembrolizumab (2017) PD-1 Solid tumor with mismatch repair deficiency or microsatellite instability
Cemiplimab (2018) PD-1 Squamous cell carcinoma
Durvalumab (2017) PD-L1 Urothelial carcinoma
Avelumab (2017) PD-L1 Merkel cell carcinoma, urothelial carcinoma
Brigatinib (2018) ALK ALK-positive NSCLC
Lorlatinib (2018) ALK ALK-positive NSCLC
Ribociclib (2017) CDK4/6 Breast cancer
Abemaciclib (2017) CDK4/6 Breast cancer
Niraparib (2017) PARP Ovarian cancer, peritoneal cancer
Dacomitinib (2018) EGFR NSCLC with EGFR exon 19 deletion or exon 21 L858R substitution mutations
Talazoparib (2018) PARP Breast cancer with germline BRCA mutations
Duvelisib (2018) PI3Kδ, PI3Kγ Chronic lymphocytic leukemia, small lymphocytic lymphoma
Larotrectinib (2018) TRKs Solid tumor with TRK gene fusion
Neratinib (2017) EGFR/HER2 HER2-amplified breast cancer

have a high selective inhibitory activity against both wild- HER2 and Its Inhibitors
types and these sensitive mutant EGFR (29). Previous studies In breast cancer, the overall HER2 mutation rate is ∼1.6% (25
show that gefitinib and erlotinib are important for the first- out of 1,499 patients). In a study by Bose et al., seven HER2
line treatment of NSCLC patients with the sensitive EGFR somatic mutations including G309A, D769H, D769Y, V777L,
mutations (30, 31). On the other hand, another mutation T790M, P780ins, V842I, and R896C, have been identified as activating
a secondary EGFR mutation emerging in NSCLC, can lead to mutations (33). Several patients with HER2 activating mutations
the resistance of more than half of patients’ TKIs treatment (32). are resistant to the reversible HER2 inhibitor lapatinib, but
Very recently, the third-generation TKI inhibitor osimertinib has sensitive to the irreversible HER2 inhibitor neratinib. Neratinib
been approved to effectively target to EGFR T790M mutation as a dual inhibitor of HER2 and EGFR was approved by FDA
with a response rate of 61% in NSCLC, significantly extending in 2017. It has been shown that the HER2 L755S mutation
the overall survival in patients with the T790M mutation (9). results in an acquired resistance to lapatinib in breast cancer,
However, the further mutation of a residue in the P-loop which could be overcome by the neratinib (34). In another
(L718Q) has been found to cause resistance to osimertinib (10). study, the HER2-T798I gatekeeper mutation in breast cancer
Nevertheless, though diverse EGFR mutations are present, the patients with a AHER2-L869R mutation was identified as a
overall survival of lung cancer patients is markedly improved mechanism of acquired resistance to neratinib (13). The trial
with TKI therapy. of neratinib has also been conducted in colorectal cancer

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Jin et al. Cancer Mutations and Targeted Therapy

(CRC) patients. The HER2 gene amplification and mutation Recently, many strategies dealing with mutation-driven drug
in CRC can lead to the resistance of EGFR-targeted therapies resistance have been proposed and evaluated both experimentally
cetuximab and panitumumab (35, 36). A negative effect of and clinically. The traditional chemotherapy concept of “one
neratinib monotherapy has recently been confirmed in 12 CRC ligand to one receptor” for a biological response is inadequate.
patients with different tumors harboring HER2 mutations (15). The treatment of a particular type of cancer with the
There were no positive therapeutic response and the median prescriptive drugs involves many special genes, interacting with
PFS was only 1.8 months, indicating that monotherapy with their respective targets and triggering a series of biological
neratinib is ineffective. The underlying mechanisms still require responses. The concept of using multi-drug therapy and seeking
further investigations. multifunctional compounds that can efficiently interact with
various targets might be feasible (47). Currently, to overcome
ALK and Different Generation of mutation-driven drug resistance, the main strategies include:
ALK Inhibitors (1) the design of new mutation-targeted compounds to restore
ALK has long been identified as a therapeutic target in cancer. wide-type protein activities, to delete mutants or to influence
The first ALK inhibitor crizotinib was approved by the FDA in downstream targets; (2) the application of combinational therapy
2011 (37). Although most NSCLC patients respond to this drug, or new compounds for multiple targeting. Here, we give some
tumors become resistant after 1–2 years of treatment. Around examples of how to overcome mutation-driven resistance of
1/3 of crizotinib-resistant tumors harbor mutations within the targeted therapy.
ALK kinase domain. The most commonly observed mutations of
L1196M and G1269A lead to a decreased affinity for crizotinib Dacomitinib, an Irreversible Pan-ERBB
(38). Other ALK point mutations, such as L1152R, C1156Y, Inhibitor, Targeting EGFR
I1171T, F1174L, G1202R, and S1206Y, are also associated with Activating Mutants
crizotinib resistance (39). Another oncoprotein of fusion-type Recently, dacomitinib was approved to use for metastatic NSCLC
tyrosine kinase, the EML4-ALK, results from the inversion within with EGFR exon 19 deletion or exon 21 L858R substitution
the short arm of the human chromosome 2 in 4–5% of cases mutations. In a randomized, multicenter, open-label, phase
of NSCLC (40). Two mutations of EML4-ALK, C1156Y, and III trial (ARCHER 1050), the patients with newly diagnosed
L1196M, confer a significant resistance to ALK inhibitors, such advanced NSCLC and one EGFR mutation (exon 19 deletion
as crizotinib and PDD (2,4-pyrimidinediamine derivative) (19). or L858R) received a 45 mg/day dose of oral dacomitinib or
The EML4-ALK C1156Y mutation can contribute to a higher a 250 mg/day gefitinib for 28 days. In the dacomitinib group,
resistance to PDD than those in the L1196M mutant form. It the progression-free survival (14.7 months, 95% CI 11.1–16.6)
is reported that a candidate ALK inhibitor TAE684 can bind to was significantly longer than that in the gefitinib group (9.2
these mutant kinases, which may have potency in overcoming months, 95% CI 9.1–11.0) (48). This investigation supports
the mutation-driven resistance (41). The new generation ALK the dacomitinib as the first line therapy for EGFR-mutation
inhibitors lorlatinib and brigatinib were approved in 2018 NSCLC patients.
for the treatment of patients with ALK-rearranged NSCLC. Dacomitinib is initially designed for irreversible pan-ERBB
Lorlatinib has been demonstrated to inhibit resistant ALK inhibition. As a small-molecule covalent binding inhibitor of
mutations, including ALK G1202R (16). However, Shaw et al. enzymatically active HER family tyrosine kinases EGFR and
showed that an ALK L1198F mutation together with the HER2, it may act as a potent inhibitor of EGFR T790M
C1156Y mutation results in the resistance of lorlatinib in a mutation (49). Additionally, dacomitinib significantly inhibits
patient with metastatic ALK-rearranged NSCLC (18). However, both wild-type and the gefitinib-resistant ERBB2 mutation in
the L1198F mutation re-sensitized crizotinib treatment of a lung cancer. Based on an in-depth investigation, dacomitinib
resistant tumor. It was demonstrated that both lorlatinib and is an effective drug that may treat NSCLC patients with a
brigatinib can overcome crizotinib resistance in NSCLC patients T790M-related acquired resistance to gefitinib or erlotinib (8).
(42, 43). Moreover, when brigatinib was combined with anti- It has been indicated that dacomitinib significantly improves
EGFR antibody, it was effective against EGFR triple-mutant cells progression-free survival in EGFR-mutation NSCLC patients and
in vitro and in vivo (44). is considered as a new treatment option for this population.

STRATEGIES FOR OVERCOMING Encorafenib/Binimetinib and

MUTATION-DRIVEN RESISTANCE Dabrafenib/Trametinib for Dual Inhibition
of BRAF and MEK
Mutations in cancer therapy targets usually result in the loss The FDA approved dabrafenib plus trametinib for the anaplastic
of functions and the accumulation of dysfunctional proteins thyroid cancer (ATC) with BRAF-V600E mutation in May
in tumors (45). Moreover, many mutants have oncogenic 2018, as well as for the adjuvant treatment of BRAF V600E/K-
gain-of-function (GOF) activities including increased tumor mutated melanoma in April 2018. Previous studies revealed that
proliferation, metastasis and drug resistance (46). Notably, tumor dabrafenib plus trametinib have shown substantial antitumor
cells that receive targeted therapy may lead to an overactivation activity in patients with previously treated BRAF-V600E mutated
of the by-pass signaling pathways to develop resistance. In most metastatic NSCLC and untreated BRAFV-600E mutated NSCLC
cases, multiple alterations are observed in a resistant tumor. (50, 51). Trametinib is an orally administered MEK1/MEK2

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Jin et al. Cancer Mutations and Targeted Therapy

inhibitor that suppresses RAF-dependent MEK phosphorylation of tumor cells (58). Currently, the main challenge for further
and persistently inhibits phosphorylated ERK (a substrate of novel drug development in targeted therapy is the clarification
MEK) (52). Dabrafenib is a reversible and high-efficiency ATP- of specific molecular mechanisms underlying the varied forms
competitive inhibitor of RAF kinases, especially the mutant of tumors in clinic. It has been acknowledged that cancer is
BRAF (53). Subbiah et al. reported that the overall response caused by a set of driver mutations. In this regard, it is of great
rate of dabrafenib plus trametinib applied in BRAF V600E- significance to: (1) identify and validate key mutant genes and
mutated ATC (complete reaction plus partial reaction to the best proteins in cancers as new targets; (2) identify patients most
overall response) is 69% (54). In contrast to BRAF inhibitor likely and unlikely to benefit from certain targeted therapies;
monotherapy, it has longer progression-free survival and overall (3) evaluate the mechanism of mutation-driven drug resistance.
survival. Overall, the most common adverse events include In past decades, several key mutations which influence drug
fatigue, pyrexia and nausea (54), consistent with previous sensitivity have been identified in various cancers. In order
reports in advanced or metastatic melanoma and NSCLC (50). to deal with mutation-driven drug resistance, new methods
Dabrafenib plus trametinib is the first regimen approved to have and drugs have been discovered and approved for clinical
significant clinical efficacy in BRAF V600E-mutated ATC. use (47). Even so, detailed individualized treatment strategies
In June 2018, the FDA approved the combination of BRAF targeting specific tumorigenesis and drug resistant mechanisms
inhibitor encorafenib and the MEK inhibitor binimetinib are still required. Advances in these areas would allow for
for treatment of patients with unresectable or metastatic more targeted and effective therapeutic options for more
melanoma with a BRAF-V600E or -V600K mutation. It is the cancer patients.
third BRAF/MEK inhibitor combination approved following
the dabrafenib/trametinib and vemurafenib/cobimetinib AUTHOR CONTRIBUTIONS
combinations (55). The main adverse events for encorafenib plus
binimetinib when applied to BRAF-V600 mutant melanoma ML, JS, JL, YZ, JW, LQ, and QW were responsible for the
are gastrointestinal reactions, including nausea, diarrhea and review of the literature. JJ, JY, XW, QZ, CC, and ML wrote the
vomiting. Additionally, this combination has a lower calorific manuscript. XW and LQ drew the Tables. XW, TY, and ZX
value and photosensitivity than other available BRAF-MEK designed the study and contributed with the valuable discussion
inhibitor combinations do (56). Considerable evidence supports and revision of the manuscript.
that the median progression-free survival was 14.9 months with
encorafenib plus binimetinib, compared with 7.3 months with FUNDING
vemurafenib (57). Therefore, it is an effective therapeutic option
in patients with unresectable or metastatic melanoma, with a This work was supported by the National Natural Science
BRAF V600E or V600K mutation. Foundation of China (Grant nos. 81503093, 81602166, and
81672444) and the Joint Funds of the Southwest Medical
CONCLUSIONS University and Luzhou (2016LZXNYD-T01, 2017LZXNYD-Z05,
and 2017LZXNYD-J09). The funding from National Natural
In the new era of targeted therapy, treatment options are Science Foundation of China (Grant nos. 81503093) will cover
increasingly based on the precise molecular and genetic profiling open access fee.

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with locally advanced or metastatic BRAF V600-mutant anaplastic and Qu. This is an open-access article distributed under the terms of the Creative
thyroid cancer. J Clin Oncol. (2018) 36:7–13. doi: 10.1200/jco.2017.7 Commons Attribution License (CC BY). The use, distribution or reproduction in
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G, et al. Overall survival in patients with BRAF-mutant melanoma with accepted academic practice. No use, distribution or reproduction is permitted
receiving encorafenib plus binimetinib versus vemurafenib orencorafenib which does not comply with these terms.

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