RESEARCH BRIEF Clinical Acquired Resistance to RAF Inhibitor Combinations in BRAF-Mutant Colorectal Cancer through MAPK Pathway Alterations

ABSTRACT BRAF mutations occur in approximately 10 % of colorectal cancers. Although RAF inhibitor monotherapy is highly effective in BRAF-mutant melanoma, response rates in BRAF-mutant colorectal cancer are poor. Recent clinical trials of combined RAF/EGFR or RAF/ MEK inhibition have produced improved effi cacy, but patients ultimately develop resistance. To iden-tify molecular alterations driving clinical acquired resistance, we performed whole-exome sequencing on paired pretreatment and postprogression tumor biopsies from patients with BRAF-mutant colorec-tal cancer treated with RAF inhibitor combinations. We identifi ed alterations in MAPK pathway gene