Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma.

ABSTRACT: The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a BRAF^V600E mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease. We employed a genetic screening approach to identify gain-of-function mechanisms of BRAFi resistance in two independent melanoma cell lines. Our screens identified both known and unappreciated drivers of BRAFi resistance, including multiple members of the DBL family. Mechanistic studies identified a DBL/RAC1/PAK signaling axis capable of driving resistance to both current and next-generation BRAFis. However, we show that the SRC inhibitor, saracatinib, can block the DBL-driven resistance. Our work highlights the utility of our straightfo

SUBMITTER: Feddersen CR 

PROVIDER: S-EPMC6774858 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature