Abstract
Osimertinib (AZD9291) has an efficacy superior to that of standard EGFR-tyrosine kinase inhibitors for the first-line treatment of patients with EGFR-mutant advanced non-small cell lung cancer (NSCLC). However, patients treated with osimertinib eventually acquire drug resistance, and novel therapeutic strategies to overcome acquired resistance are needed. In clinical or preclinical models, several mechanisms of acquired resistance to osimertinib have been elucidated. However, the acquired resistance mechanisms when osimertinib is initially used for EGFR-mutant NSCLC remain unclear. In this study, we experimentally established acquired osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines and investigated the molecular profiles of resistant cells to uncover the mechanisms of acquired resistance. Various resistance mechanisms were identified, including the acquisition of MET amplification, EMT induction, and the upregulation of AXL. Using targeted next-generation sequencing with a multigene panel, no secondary mutations were detected in our resistant cell lines. Among three MET-amplified cell lines, one cell line was sensitive to a combination of osimertinib and crizotinib. Acquired resistance cell lines derived from H1975 harboring the T790M mutation showed AXL upregulation, and the cell growth of these cell lines was suppressed by a combination of osimertinib and cabozantinib, an inhibitor of multiple tyrosine kinases including AXL, both in vitro and in vivo. Our results suggest that AXL might be a therapeutic target for overcoming acquired resistance to osimertinib. IMPLICATIONS: Upregulation of AXL is one of the mechanisms of acquired resistance to osimertinib, and combination of osimertinib and cabozantinib might be a key treatment for overcoming osimertinib resistance.
Highlights
Lung cancer remains the leading cause of cancer mortality worldwide, and non–small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers, with 50% of these being adenocarcinomas [1,2,3]
On the basis of the example of cisplatin resistance study in which the resistant cells were established using two methods [23], we previously reported that these methods of drug exposure in cell culture provide the different mechanisms of acquired resistance to first- and second-generation EGFR-TKIs [24, 25]
HCC4011) with TKI-sensitive EGFR mutations were exposed to osimertinib using two different methods: stepwise escalation (ORS series) and high-concentration exposure (ORH series)
Summary
Lung cancer remains the leading cause of cancer mortality worldwide, and non–small cell lung cancer (NSCLC) accounts for more than 85% of all lung cancers, with 50% of these being adenocarcinomas [1,2,3]. EGFR mutations, such as L858R point mutations and exon 19 deletions, occur in approximately 10% to 15% and 40% of NSCLC cases in Western and Asian populations, respectively [4]. Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/). Tyrosine-kinase inhibitors (EGFR-TKIs: gefitinib, erlotinib, and afatinib) are recommended as standard treatments for patients with advanced NSCLC [5, 6]. Acquired resistance develops within about a year in most cases [7]. Secondary EGFR T790M mutation, detected in about half of such cases, is the most common mechanism of TKI resistance [8, 9]
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