Data from MERTK Promotes Resistance to Irreversible EGFR Tyrosine Kinase Inhibitors in Non–small Cell Lung Cancers Expressing Wild-type <i>EGFR</i> Family Members

Abstract

<div>AbstractPurpose:<p>Lung cancer is the leading cause of cancer-related death. Non–small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and over 60% express wild-type <i>EGFR</i> (<i>wtEGFR</i>); however, EGFR tyrosine kinase inhibitors (TKIs) have limited effect in most patients with <i>wtEGFR</i> tumors. We previously identified MERTK tyrosine kinase as a potential therapeutic target in NSCLC and developed MRX-2843, a novel MERTK-selective inhibitor with favorable properties for clinical translation. The goal of this study was to determine whether MERTK and EGFR inhibitor combination therapy could provide antitumor efficacy against <i>wtEGFR</i> NSCLC.</p>Experimental Design:<p> An unbiased screen of 378 kinase inhibitors was conducted to identify synergistic interactions with MRX-2843 and biochemical and therapeutic effects were determined <i>in vitro</i> and <i>in vivo</i>.</p>Results:<p>Numerous irreversible EGFR TKIs, including CO-1686 and osimertinib, synergized with MRX-2843 to inhibit <i>wtEGFR</i> NSCLC cell expansion, irrespective of driver oncogene status. CO-1686 and MRX-2843 combination therapy inhibited MERTK, wtEGFR, and ERBB2/ERBB3 and decreased downstream PI3K-AKT, MAPK-ERK, and AURORA kinase (AURK) signaling more effectively than single agents. Inhibition of PI3K, AKT or AURK, but not MEK, synergized with CO-1686 to inhibit tumor cell expansion, suggesting their roles as key redundant resistance pathways. Treatment with MRX-2843 and CO-1686 or osimertinib prevented xenograft growth while single agents had limited effect. Tumor growth inhibition was durable even after treatment with combination therapy was stopped.</p>Conclusions:<p>Our data support the application of MRX-2843 in combination with an irreversible EGFR TKI as a novel strategy for treatment of patients with <i>wtEGFR</i> NSCLC.</p></div>