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Ref Type Journal Article
PMID (32669268)
Authors Tung JK, Neishaboori N, Haraldsdottir S, Suarez CJ
Title An amino-terminal BRAF deletion accounting for acquired resistance to RAF/EGFR inhibition in colorectal cancer.
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
BRAF V47_M438del deletion gain of function - predicted BRAF V47_M438del results in the deletion of 392 amino acids of the Braf protein from amino acids 47 to 438 (UniProt.org). V47_M438del (reported as internal deletion of exons 2-10) has been associated with acquired resistance to a Braf inhibitor in a patient (PMID: 32669268), and is predicted to lead to a gain of Braf protein function due to the deletion of the CR1 autoinhibitory domain and preservation of the protein kinase domain (PMID: 23890088, PMID: 22113612, PMID: 29171936). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
BRAF V47_M438del BRAF V600E colon adenocarcinoma predicted - resistant Cetuximab + Irinotecan + Vemurafenib Case Reports/Case Series Actionable In a clinical case study, BRAF V47_M438del (reported as deletion of exons 2-10) was identified in the post-progression biopsy of a patient with colon adenocarcinoma harboring BRAF V600E, who previously responded to the combination of Captosar (irinotecan), Erbitux (cetuximab), and Zelboraf (vemurafenib) (PMID: 32669268). 32669268