Exploiting YES1-Driven EGFR Expression Improves the Efficacy of EGFR Inhibitors

Epidermal growth factor receptor (EGFR) is a highly expressed driver of many cancers, yet the utility of EGFR inhibitors (EGFRi) is currently limited to cancers that harbor sensitizing mutations in the EGFR gene. Rather than conventionally blocking the kinase activity of EGFR, we sought to disrupt its transcription as an alternative approach. 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. We leveraged this finding to reveal that selective YES1 and EGFR inhibitors are highly synergistic using in vitro and in vivo in models of TNBC and NSCLC. Together, these data provide a rationale for blocking YES1 activity as an approach for improving the efficacy of EGFR-targeting drugs in tumors that are normally resistant to these agents.