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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.
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 ( 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