title: Cooperation of BRAF(F595L) and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling.
abstract: 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.
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kordes
authors.affiliation: Institute of Molecular Medicine and Cell Research, Faculty of Medicine, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Röring
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|DKTK, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Heining
authors.affiliation: Institute of Molecular Medicine and Cell Research, Faculty of Medicine, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Braun
authors.affiliation: DKTK, Heidelberg, Germany.|Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|DKTK, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Richter
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|DKTK, Heidelberg, Germany.|DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Geörg
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|DKTK, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Scholl
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|DKTK, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Gröschel
authors.affiliation: Institute of Pathology, Heidelberg University Hospital and NCT Heidelberg, Heidelberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Roth
authors.affiliation: Institute of Pathology, Comprehensive Cancer Center Mainfranken, University of Würzburg and Würzburg University Hospital, Würzburg, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Institute of Pathology, Comprehensive Cancer Center Mainfranken, University of Würzburg and Würzburg University Hospital, Würzburg, Germany.
authors.forename: E
authors.initials: E
authors.lastname: Geissinger
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|DKTK, Heidelberg, Germany.|DKFZ-Heidelberg Center for Personalized Oncology (HIPO), Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: von Kalle
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: D
authors.initials: D
authors.lastname: Jäger
authors.affiliation: DKTK, Heidelberg, Germany.|Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, Heidelberg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Brors
authors.affiliation: DKTK, Heidelberg, Germany.|Institute of Pathology, Heidelberg University Hospital and NCT Heidelberg, Heidelberg, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Weichert
authors.affiliation: Department of Medical Oncology, National Center for Tumor Diseases (NCT), Heidelberg, Germany.|Department of Internal Medicine VI, Heidelberg University Hospital, Heidelberg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Grüllich
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|DKTK, Heidelberg, Germany.
authors.forename: H
authors.initials: H
authors.lastname: Glimm
authors.affiliation: Institute of Molecular Medicine and Cell Research, Faculty of Medicine, BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Brummer
authors.affiliation: Department of Translational Oncology, NCT Heidelberg, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Section for Personalized Oncology, Heidelberg University Hospital, Heidelberg, Germany.|DKTK, Heidelberg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Fröhling
mesh_terms: D000328:Adult; D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D015153:Blotting, Western; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D059472:Exome / Q000235:genetics; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D054747:Histiocytic Sarcoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation / Q000235:genetics*; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015398:Signal Transduction
chemical_list: D014408:Biomarkers, Tumor; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)