Increased Synthesis of MCL-1 Protein Underlies Initial Survival of <i>EGFR</i>-Mutant Lung Cancer to EGFR Inhibitors and Provides a Novel Drug Target.

Abstract

<b>Purpose:</b> EGFR inhibitors (EGFRi) are effective against <i>EGFR</i>-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, <i>T790M</i> We recently demonstrated that <i>T790M</i> can arise <i>de novo</i> during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like <i>T790M</i> <b>Experimental Design:</b> We have developed DTCs to EGFRi in <i>EGFR</i>-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink <i>EGFR</i>-mutant lung cancer tumors <i>in vivo</i> <b>Results:</b> We demonstrate surviving <i>EGFR</i>-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early <i>EGFR</i>-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both <i>in vitro</i> and <i>in vivo</i> <b>Conclusions:</b> Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. <i>Clin Cancer Res; 24(22); 5658-72. ©2018 AACR</i>.