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ERK inhibition effectively overcomes acquired resistance of epidermal growth factor receptor‐mutant non–small cell lung cancer cells to osimertinib
Author(s) -
Li Yiting,
Zang Hongjing,
Qian Guoqing,
Owonikoko Taofeek K.,
Ramalingam Suresh R.,
Sun ShiYong
Publication year - 2020
Publication title -
cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.052
H-Index - 304
eISSN - 1097-0142
pISSN - 0008-543X
DOI - 10.1002/cncr.32655
Subject(s) - osimertinib , t790m , cancer research , mapk/erk pathway , erlotinib , epidermal growth factor receptor , medicine , epidermal growth factor , cell growth , afatinib , biology , cancer , gefitinib , kinase , microbiology and biotechnology , receptor , genetics
Background Osimertinib (AZD9291), a third‐generation, mutation‐selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR‐TKI), is an approved drug for patients who have non–small cell lung cancer (NSCLC) with activating EGFR mutations or those harboring a resistant T790M mutation. Unfortunately, all patients eventually relapse and develop resistance to osimertinib. The current study addressed whether ERK inhibition exerts effects similar to those produced by MEK inhibition in overcoming acquired resistance to osimertinib. Methods Drug effects on cell and tumor growth were assessed by measuring cell number alterations and colony formation in vitro and with xenografts in nude mice in vivo. Apoptosis was assessed with annexin V/flow cytometry and protein cleavage. Protein alterations in cells were detected with Western blot analysis. Gene overexpression and knockout were achieved with lentiviral infection and CRISPR/Cas9, respectively. Results The combination of osimertinib with an ERK inhibitor synergistically decreased the survival of osimertinib‐resistant cell lines with enhanced induction of apoptosis and effectively inhibited the growth of osimertinib‐resistant xenografts in nude mice. Moreover, the combination of an MEK or ERK inhibitor with a first‐generation (eg, erlotinib) or second‐generation (eg, afatinib) EGFR‐TKI also very effectively inhibited the growth of osimertinib‐resistant cells in vitro and of tumors in vivo, although these cell lines were cross‐resistant to first‐generation or second‐generation EGFR‐TKIs. Conclusions The current findings emphasize the importance of targeting MEK/ERK signaling in maintaining the long‐term benefit of osimertinib through overcoming acquired resistance to osimertinib, warranting further investigation of this therapeutic strategy to improve the therapeutic efficacy of osimertinib in the clinic.