Increased synthesis of Mcl-1 protein underlies initial survival of EGFR-mutant lung cancer to EGFR inhibitors and provides a novel drug target

Purpose: EGFR inhibitors (EGFRi) are effective agains EGFR-mutant lung cancers. The efficacy of these drugs, how ever, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo 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 acquir ing secondary mutations like T790M. Experimental Design: We have developed DTCs to EGFR in EGFR-mutant lung cancer cell lines. Subsequent analyses o DTCs included RNA-seq, high-content microscopy, and pro tein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhi bitors to eliminate DTCs and shrink EGFR-mutant lung cance tumors in vivo. Results: We demonstrate surviving EGFR-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 EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo. Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy.