Reactivation of MAPK Signaling Contributes to Insensitivity of BRAF-Mutant Colorectal Cancers to RAF Inhibition with Vemurafenib

BRAF mutations occur in 10% to 15% of colorectal cancers and confer adverse outcome in the metastatic setting. Although RAF inhibitors such as vemurafenib (PLX4032) have proven effective in the treatment of BRAF-mutant melanoma, they are surprisingly ineffective in BRAF-mutant colorectal cancers, and the reason for this disparity remains unclear. Compared with BRAF-mutant melanoma cells, BRAF-mutant colorectal cancer cells were less sensitive to vemurafenib, and phospho-extracellular signal-regulated kinase (P-ERK) suppression was not sustained in response to treatment. Although transient inhibition of P-ERK by vemurafenib was observed in colorectal cancer, rapid ERK reactivation occurred through epidermal growth factor receptor (EGFR)-mediated activation of RAS and CRAF. BRAF-mutant colorectal cancers expressed greater levels of phospho-EGFR than BRAF-mutant melanomas, suggesting that colorectal cancers are specifically poised for EGFR-mediated resistance. Combined RAF and EGFR inhibition blocked reactivation of mitogen-activated protein kinase (MAPK) signaling in BRAF-mutant colorectal cancer cells and markedly improved efficacy in vitro and in vivo. These findings support the evaluation of combined RAF and EGFR inhibition in patients with BRAF-mutant colorectal cancer.