An amino-terminal BRAF deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer

Although combination therapy with RAF and EGFR inhibitors has improved the survival outcomes of patients with BRAF-mutated colorectal cancer (CRC), acquired resistance invariably develops. The mechanisms of acquired resistance to RAF inhibitors have been largely attributed to activating mutations in RASgenes, MAP2K mutations, and amplifications in BRAF, RAS genes, and EGFR. In this report, we describe a patient with BRAF-mutated CRC who acquired an amino-terminal BRAF deletion involving the Ras-binding domain (RBD) after treatment with RAF/EGFR inhibitor therapy. Amino-terminal BRAF deletions involving the RBD are a rare mechanism of acquired resistance to RAF inhibitors, particularly in CRC for which there is only one prior report in the literature.