Exploiting YES1-driven EGFR expression improves the efficacy of EGFR inhibitors.

Abstract

Epidermal growth factor receptor (EGFR) is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors is limited to cancers that harbor sensitizing mutations in the EGFR gene due to dose limiting toxicities. Rather than conventionally blocking the kinase activity of EGFR, we sought to reduce its transcription as an alternative approach to broaden the therapeutic window for EGFR inhibitors targeting wildtype or mutant EGFR. We found that YES1 is highly expressed in triple negative breast cancer (TNBC) and drives cell growth by elevating EGFR levels. Mechanistically, YES1 stimulates EGFR expression by signaling to JNK and stabilizing the AP-1 transcription factor, c-Jun. This effect extends beyond TNBC as YES1 also sustains EGFR expression in non-small cell lung cancer (NSCLC) cells, including those that harbor the EGFR gatekeeper mutation, T790M. The novel ability of YES1 to regulate the expression of wildtype and mutant EGFR mRNA and protein provides a potential therapeutic opportunity of utilizing YES1 blockade to broadly increase the efficacy of EGFR inhibitors. Indeed, we found synergy within in vitro and in vivo models of TNBC and NSCLC, even in the absence of EGFR activating mutations. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in cancers that have generally been refractory to such inhibitors. Implications: YES1 sustains EGFR expression, revealing a therapeutic vulnerability for increasing the efficacy of EGFR inhibitors by lowering the threshold for efficacy in tumors driven by wildtype or mutant receptor.