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Strategies to Overcome Bypass Mechanisms Mediating Clinical Review Molecular Cancer Therapeutics Strategies to Overcome Bypass Mechanisms Mediating Clinical Resistance to EGFR Tyrosine Kinase Inhibition in Lung Cancer Hatim Husain, Michael Scur, Ayesha Murtuza, Nam Bui, Brian Woodward, and Razelle Kurzrock Abstract The vast majority of patients with metastatic lung cancers fication, increased expression of AXL, BIM modulation, NF-kB who initially benefit from EGFR-targeted therapies eventually activation, histologic switch to small-cell cancer, epithelial-to- develop resistance. An increasing understanding of the number mesenchymal transition, PDL1 expression with subsequent and complexity of resistance mechanisms highlights the chal- immune tolerance, and release of cytokines such as TGFb and lenge of treating tumors resistant to EGFR inhibitors. Resistance IL6. Herein, we review the growing body of knowledge regard- mechanisms include new, second-site mutations within EGFR ing EGFR bypass pathways, and the development of new drugs (e.g., T790M and C797S), upregulation of MET kinase, upre- and combination treatment strategies to overcome resistance. gulation of insulin growth factor receptor (IGFR), HER2 ampli- Mol Cancer Ther; 16(2); 265–72. Ó2017 AACR. Introduction EGFR Signaling and Aberrations Receptor tyrosine kinases (RTK) function as key regulators of EGFR (also known as ERBB1 or HER1) belongs to the ERBB cell growth, proliferation, and survival by transducing signals family of cell-surface RTKs that also includes HER2 (also known as initiated by growth factors to the MEK/ERK, PI3K/AKT, and STAT NEU or ERBB2; ref. 16). EGF binding to EGFR triggers homo- pathways. dimerization or heterodimerization of this receptor with other Activation of RTKs is reversible and tightly regulated, and the ERBB members, namely HER2, receptor phosphorylation, and cells are dependent on extracellular cues from the environment. activation of downstream effectors such as RAS–RAF–MEK–ERK However, in cancer cells, these pathways are often constitutive- and PI3K–AKT–mTOR, leading to cell proliferation (16). Other ly activated due to genetic alterations in either RTKs themselves EGFR ligands include TGFa, amphiregulin, b-cellulin, heparin- or components of the downstream signaling pathways (1). binding EGF, and epiregulin (17). These alterations can result in constitutive signaling that lead The common EGFR mutations, such as exon 19 deletions and to increased cell growth and survival, all of which are hallmarks the exon 21 L858R, which account for about 85% of all EGFR of cancer (2). Inhibition of the mutant kinases by EGFR mutations, predict sensitivity to afatinib and dacomitinib (irre- tyrosine inhibitors leads to simultaneous suppression of mul- versible EGFR TKI) as well as gefitinib and erlotinib (reversible tiple pathways, frequently resulting in cell growth arrest and EGFR TKIs) in patients with lung cancer (18). Less common death (3, 4). A number of different pathways to acquired aberrations besides exon 19 deletions and L858R include resistance have been described, and include development of G719X and L861X that together make up 5% of EGFR mutations resistant second-site EGFR mutations, or activation of alterna- (ref. 19; Table 1). In contrast, exon 20 insertions or T790M tive pathways through mutation, amplification, or other mutations are resistant to most first-generation EGFR TKIs given mechanisms (Table 1; refs. 3, 5–15). as monotherapy. Data suggest that there may be two routes to developing T790M resistance: one that is selected for over time from preexisting T790M mutation in cells and a second that is acquired at a later time in initially T790M-negative EGFR-mutated cells (20). Strategies are underway to evaluate combinations of Division of Hematology and Oncology, Center for Personalized Cancer Therapy, anti-EGFR tyrosine kinase inhibitors and mAbs that may be used University of California, San Diego, Moores Cancer Center, La Jolla, California. for patients with T790M mutations or exon 20 insertions. Of Note: Supplementary data for this article are available at Molecular Cancer interest in this regard, exon 20 insertions may increase EGFR Therapeutics Online (http://mct.aacrjournals.org/). dimerization, creating a susceptibility to EGFR antibodies (6). Corresponding Authors: Razelle Kurzrock, University of California San Diego, Third-generation anti-EGFR TKIs are irreversible inhibitors and Moores Cancer Center, 3855 Health Sciences Dr., MC #0658, La Jolla, CA 92093. include, but are not limited to, osimertinib (AZD9291; approved Phone: 858-246-1102; Fax: 858-246-1915; E-mail: [email protected]; and by the FDA), rocelitinib (CO-1686; C27H28F3N7O3), ASP8273, Hatim Husain, [email protected] PF7775, and EGF816 (C26H31ClN6O2; refs. 21, 22; Supplemen- doi: 10.1158/1535-7163.MCT-16-0105 tary Fig. S1). These molecules were developed to have high Ó2017 American Association for Cancer Research. potency against the first-generation EGFR TKI-resistant mutation www.aacrjournals.org 265 Downloaded from mct.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Husain et al. Table 1. EGFR-activating and resistance mutations in adenocarcinoma of the lung Frequency in EGFR- Response rate to Median PFS after Median OS after mutant lung first-generation first-generation first-generation Mutation adenocarcinoma (%) EGFR TKIs (%) TKIs (months) TKIs (months) Comment References Exon 19 deletions 45 60–85 9–15 24–34 5, 7, 9, 10 L858R (exon 21) 40 50–67 8–11 21 5, 7, 10 Exon 20 insertions 2–9 NA NA Varies widely 4–16 May increase 6, 7, 8 months dimerization and sensitize to EGFR antibody G719X (Exon 18) 3 37 NA NA 11 L861X (exon 21) 2 40 NA NA 11 Exon 19 insertions 1 NA NA NA Case series report 12 responsiveness to erlotinib T790M (exon 20) 25% in de novo Resistant to first-generation NA NA About half of the 3, 13–15 patients TKIs patients with Response rate to third- acquired resistance generation EGFR TKI develop T790M AZD9291 is 61% Abbreviations: Mo, months; NA, not available; OS, overall survival; PFS, progression-free survival. T790M, and active areas of research are focusing on identifying raises the possibility that these resistant cells exist at low mechanisms of resistance to these compounds. frequency before treatment (27). Although early-phase studies of the combination of MET Acquired Resistance to EGFR-targeted and EGFR inhibitors held promise for this combination, larger phase III studies showed less clear signals of efficacy (28, 29). A Therapies recently reported phase III study of the MET kinase inhibitor Tumor progression on targeted therapy may be the product tivantinib (ARQ197) and erlotinib versus erlotinib and pla- of both intrinsic and acquired resistance (20). In addition, drug cebo recruited 1,048 patients, but failed to meet its primary dosing, pharmacokinetics, and administration may explain objective, with a HR of 0.98 for overall survival. This result is why some patients do not respond to anti-EGFR TKI therapies. perhaps related to the fact that the patients with lung cancer on When EGFR TKIs are coadministered with drugs such as the the trial were not selected for EGFR mutations or MET aberra- cholesterol-modifying medication fenofibrate that induce tions (28). A phase II study of the MET inhibitor onartuzumab CYP3A4, erlotinib metabolism is increased (23). In contrast, in combination with erlotinib in MET-amplified, EGFR- proton pump inhibitors and H2-receptor antagonists decrease uncharacterized patients showed improvement in progres- pH-dependent drug solubility, and erlotinib drug levels may be sion-free survival (PFS; HR 0.53; P ¼ 0.04) and overall survival decreased and responses attenuated (24). Although pharma- (OS; HR 0.37; P ¼ 0.002), and a companion biomarker cokinetic factors are important as we consider combinatorial analysis was done comparing MET IHC, FISH, PCR, and ELISA, strategies, we will focus on the cell-intrinsic bypass mechanisms and found that IHC was the only significant predictor of OS of acquired resistance below (Fig. 1). and PFS benefit (30). A phase I study of INC280 (an oral MET inhibitor with preclinical activity in EGFR-mutant/MET- MET activated NSCLC) had 6 of 41 patients respond when selected One of the earliest suggestions that RTK bypass signaling on the basis of MET amplification (FISH 5 copy number) or could promote resistance to targeted therapies came in the IHC of 2/3þ (31). A dose-finding phase I/II study of 25 setting of EGFR-mutant non–small cell lung cancer (NSCLC). patients receiving crizotinib and erlotinib demonstrated that In lung adenocarcinoma treated with anti-EGFR TKI therapy, one patient achieved PR and nine attained stable disease. amplification of the MET gene encoding the MET kinase has Coadministration of both drugs increased erlotinib AUC been observed in cancers with acquired resistance to EGFR TKIs, by 1.8-fold and a MTD of erlotinib 100 mg daily and crizotinib but not in the pretreatment samples (25, 26). MET amplifica- 150 mg twice daily was defined (32). Resistance to the tion was initially discovered in an EGFR-mutant cell line that third-generation anti-EGFR compounds has also been associ- was cultured in the presence of gefitinib until resistance devel- ated with MET amplification (33). Studies have started to oped. MET was found to promote resistance by reactivating evaluate the combination of MET-directed therapy and both PI3K/AKT and MEK/ERK signaling, despite the inhibition third-generation anti-EGFR TKI therapy post progression on of EGFR (27). The combination of a MET and an EGFR first-
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