BRAF inhibitors synergize with BH3 mimetics to induce apoptosis in BRAF mutant colorectal cancer cells

Abstract

Abstract Activating mutations in BRAF (BRAFV600E) occur in ~10% of colorectal cancers (CRCs) and drive tumorigenesis through constitutive activation of MAPK signaling. In metastatic CRC, BRAF mutations are associated with poorer prognosis and resistance to conventional therapies, necessitating an urgent need to develop new treatments for these patients. BRAF inhibitors such as vemurafenib and dabrafenib have significant clinical activity in BRAF-mutant melanoma, however BRAF-mutant CRCs are largely refractory to these agents, due at least in part to feedback-relief mediated reactivation of MAPK signaling or alternate signaling pathway activation. Strategies to enhance the a..