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Transcriptional control and signal transduction, cell cycle

Cooperation of BRAFF595L 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 D594F595G596 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, BRAFF595L 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 BRAFF595L, 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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Acknowledgements

We thank the DKFZ-HIPO and NCT Precision Oncology Program (POP) Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility and the DKFZ-HIPO Data Management Group for technical support and expertise. We also thank Katja Beck, Janna Kirchhof, Stephan Wolf, Roland Eils and Peter Lichter for infrastructure and program development within DKFZ-HIPO and NCT POP; and Andreas von Deimling for the VE1 antibody. Tissue samples were provided by the NCT Heidelberg Tissue Bank in accordance with its regulations and after approval by the Ethics Committee of Heidelberg University. This work was supported by grant H021 from DKFZ-HIPO and NCT POP (CH, HG and SF), an e:Bio grant from the German Federal Ministry of Education and Research (MR and TB), Emmy Noether and Heisenberg Fellowships from the German Research Foundation (CS and TB) and the BIOSS Centre for Biological Signalling Studies funded by the Excellence Initiative of the German federal and state governments (Excellence Cluster 294).

Author contributions

MK, MR, CH, SB, BH, CS, WR and WW acquired data, analyzed data and wrote the manuscript. DR, CG, SG, AR, EG, CvK, DJ, BB and CG acquired data and analyzed data. HG, TB and SF designed the study, acquired data, analyzed data and wrote the manuscript.

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Correspondence to S Fröhling.

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Kordes, M., Röring, M., Heining, C. et al. Cooperation of BRAFF595L and mutant HRAS in histiocytic sarcoma provides new insights into oncogenic BRAF signaling. Leukemia 30, 937–946 (2016). https://doi.org/10.1038/leu.2015.319

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