Reference Detail

Ref Type

Journal Article

PMID

(26582644)

Authors

Kordes M, Röring M, Heining C, Braun S, Hutter B, Richter D, Geörg C, Scholl C, Gröschel S, Roth W, Rosenwald A, Geissinger E, von Kalle C, Jäger D, Brors B, Weichert W, Grüllich C, Glimm H, Brummer T, Fröhling S

Title

Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Leukemia	30	4	2016 Apr	937-46	Leukemia

URL

Abstract Text

Activating BRAF mutations, in particular V600E/K, drive many cancers and are considered mutually exclusive with mutant RAS, whereas inactivating BRAF mutations in the D(594)F(595)G(596) motif cooperate with RAS via paradoxical MEK/ERK activation. Due to the increasing use of comprehensive tumor genomic profiling, many non-V600 BRAF mutations are being detected whose functional consequences and therapeutic actionability are often unknown. We investigated an atypical BRAF mutation, F595L, which was identified along with mutant HRAS in histiocytic sarcoma and also occurs in epithelial cancers, melanoma and neuroblastoma, and determined its interaction with mutant RAS. Unlike other DFG motif mutants, BRAF(F595L) is a gain-of-function variant with intermediate activity that does not act paradoxically, but nevertheless cooperates with mutant RAS to promote oncogenic signaling, which is efficiently blocked by pan-RAF and MEK inhibitors. Mutation data from patients and cell lines show that BRAF(F595L), as well as other intermediate-activity BRAF mutations, frequently coincide with mutant RAS in various cancers. These data define a distinct class of activating BRAF mutations, extend the spectrum of patients with systemic histiocytoses and other malignancies who are candidates for therapeutic blockade of the RAF-MEK-ERK pathway and underscore the value of comprehensive genomic testing for uncovering the vulnerabilities of individual tumors.

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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	F595L	missense	loss of function	BRAF F595L lies within the protein kinase domain of the Braf protein (UniProt.org). F595L results in reduced Braf kinase activity (PMID: 28783719, PMID: 15035987), but works cooperatively with oncogenic Ras to activate MEK/ERK signaling, and is transforming in cell culture (PMID: 15035987, PMID: 26582644, PMID: 29533785).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF F595L	Advanced Solid Tumor	resistant	Vemurafenib	Preclinical - Cell culture	Actionable	In a preclinical study, treatment with Zelboraf (vemurafenib) did not reduce activation of Mek and Erk by BRAF F595L in transformed cells in culture (PMID: 26582644).	26582644