Reference Detail

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.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Cold Spring Harbor molecular case studies	6	4	2020 Aug		Cold Spring Harb Mol Case Stud

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