Identification of Genetic Mutations in Cancer: Challenge and Opportunity in the New Era of Targeted Therapy

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, mutations in cancer therapy targets may increase drug sensitivity, or more frequently Biodonostia Health Research Institute, 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 dabrafenib/trametinib). In this perspective, we focus on the most up-to-date knowledge [email protected] of targeted therapy and describe how genetic mutations influence the sensitivity of † These authors have contributed targeted therapy, highlighting the challenges faced within this era of precision medicine. equally to the work 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 for cancer patients. Cancer Molecular Targets and 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 Frontiers in Oncology | www.frontiersin.org 1 April 2019 | Volume 9 | Article 263 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 INFLUENCE OF GENETIC MUTATION ON breast cancer (25). It is indicated that T47D cells that become 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 Table 1 may result in the emergence of a resistance to CDK 4/6 can increase or decrease drug sensitivity ( ). 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

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