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. SIGNIFICANCE: BRAF valine 600 (V600) mutations occur in 10% to 15% of colorectal cancers, yet these tumors show a surprisingly low clinical response rate (~5%) to selective RAF inhibitors such as vemurafenib, which have produced dramatic response rates (60%-80%) in melanomas harboring the identical BRAF V600 mutation. We found that EGFR-mediated MAPK pathway reactivation leads to resistance to vemurafenib in BRAF-mutant colorectal cancers and that combined RAF and EGFR inhibition can lead to sustained MAPK pathway suppression and improved efficacy in vitro and in tumor xenografts. © 2012 American Association for Cancer Research.
Corcoran, R. B., Ebi, H., Turke, A. B., Coffee, E. M., Nishino, M., Cogdill, A. P., … Engelman, J. A. (2012). EGFR-mediated reactivation of MAPK signaling contributes to insensitivity of BRAF-mutant colorectal cancers to RAF inhibition with vemurafenib. Cancer Discovery, 2(3), 227–235. https://doi.org/10.1158/2159-8290.CD-11-0341