Loss of ACK1 Upregulates EGFR and Mediates Resistance to BRAF Inhibition

Targeted BRAF(V600E) suppression by selective BRAF inhibitors (BRAFis; e.g., vemurafenib and dabrafenib) has led to a sea change in the treatment of metastatic melanoma. Despite frequent upfront responses, acquired resistance has compromised long-term applicability. Among the various mechanisms of resistance, activation of multiple receptor tyrosine kinases is a known critical factor that contributes to vemurafenib resistance. EGFR activation has been recurrently identified in a set of vemurafenib-resistant melanomas, but little is known about how EGFR, or possibly other receptor tyrosine kinases, becomes activated. Here, we report that ACK1, a protein kinase that modulates EGFR turnover, is downregulated in vemurafenib-resistant melanoma cells. We also found that ACK1 depletion with short hairpin RNA decreased EGFR degradation when activated by epidermal growth factor, increased EGFR protein expression, and conferred resistance to BRAFis both in vitro and in vivo. Vemurafenib resistance mediated by ACK1 inhibition can be reversed by the EGFR inhibitor gefitinib. Our data indicate that ACK1 loss may be a post-transcriptional mechanism that increases EGFR signaling and contributes to drug resistance.

Automated summary

Targeted suppression of BRAF(V600E) by BRAF inhibitors has revolutionized the treatment of metastatic melanoma, but acquired resistance remains a major challenge. In vemurafenib-resistant melanomas, downregulation of ACK1, a protein kinase involved in EGFR turnover, leads to increased EGFR signaling and drug resistance. Inhibition of ACK1-mediated resistance can be reversed by the EGFR inhibitor gefitinib.