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@ARTICLE{Kordes:128945,
      author       = {M. Kordes and M. Röring and C. Heining$^*$ and S. Braun
                      and B. Hutter$^*$ and D. Richter$^*$ and C. Geörg$^*$ and
                      C. Scholl$^*$ and S. Gröschel$^*$ and W. Roth$^*$ and A.
                      Rosenwald and E. Geissinger and C. von Kalle$^*$ and D.
                      Jäger$^*$ and B. Brors$^*$ and W. Weichert and C. Grüllich
                      and H. Glimm$^*$ and T. Brummer and S. Fröhling$^*$},
      title        = {{C}ooperation of {BRAF}({F}595{L}) and mutant {HRAS} in
                      histiocytic sarcoma provides new insights into oncogenic
                      {BRAF} signaling.},
      journal      = {Leukemia},
      volume       = {30},
      number       = {4},
      issn         = {1476-5551},
      address      = {Basingstoke},
      publisher    = {Nature Publ. Group},
      reportid     = {DKFZ-2017-04957},
      pages        = {937 - 946},
      year         = {2016},
      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.},
      keywords     = {Biomarkers, Tumor (NLM Chemicals) / BRAF protein, human
                      (NLM Chemicals) / Proto-Oncogene Proteins B-raf (NLM
                      Chemicals) / HRAS protein, human (NLM Chemicals) /
                      Proto-Oncogene Proteins p21(ras) (NLM Chemicals)},
      cin          = {G100 / G200 / G102 / G010 / G150 / L101 / L601 / D120 /
                      G240},
      ddc          = {610},
      cid          = {I:(DE-He78)G100-20160331 / I:(DE-He78)G200-20160331 /
                      I:(DE-He78)G102-20160331 / I:(DE-He78)G010-20160331 /
                      I:(DE-He78)G150-20160331 / I:(DE-He78)L101-20160331 /
                      I:(DE-He78)L601-20160331 / I:(DE-He78)D120-20160331 /
                      I:(DE-He78)G240-20160331},
      pnm          = {317 - Translational cancer research (POF3-317)},
      pid          = {G:(DE-HGF)POF3-317},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:26582644},
      doi          = {10.1038/leu.2015.319},
      url          = {https://inrepo02.dkfz.de/record/128945},
}