Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS Journal Article

Authors: Yao, Z.; Yaeger, R.; Rodrik-Outmezguine, V. S.; Tao, A.; Torres, N. M.; Chang, M. T.; Drosten, M.; Zhao, H.; Cecchi, F.; Hembrough, T.; Michels, J.; Baumert, H.; Miles, L.; Campbell, N. M.; De Stanchina, E.; Solit, D. B.; Barbacid, M.; Taylor, B. S.; Rosen, N.
Article Title: Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS
Abstract: Approximately 200 BRAF mutant alleles have been identified in human tumours. Activating BRAF mutants cause feedback inhibition of GTP-bound RAS, are RAS-independent and signal either as active monomers (class 1) or constitutively active dimers (class 2). Here we characterize a third class of BRAF mutants - those that have impaired kinase activity or are kinase-dead. These mutants are sensitive to ERK-mediated feedback and their activation of signalling is RAS-dependent. The mutants bind more tightly than wild-type BRAF to RAS-GTP, and their binding to and activation of wild-type CRAF is enhanced, leading to increased ERK signalling. The model suggests that dysregulation of signalling by these mutants in tumours requires coexistent mechanisms for maintaining RAS activation despite ERK-dependent feedback. Consistent with this hypothesis, melanomas with these class 3 BRAF mutations also harbour RAS mutations or NF1 deletions. By contrast, in lung and colorectal cancers with class 3 BRAF mutants, RAS is typically activated by receptor tyrosine kinase signalling. These tumours are sensitive to the inhibition of RAS activation by inhibitors of receptor tyrosine kinases. We have thus defined three distinct functional classes of BRAF mutants in human tumours. The mutants activate ERK signalling by different mechanisms that dictate their sensitivity to therapeutic inhibitors of the pathway. © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
Journal Title: Nature
Volume: 548
Issue: 7666
ISSN: 0028-0836
Publisher: Nature Publishing Group  
Date Published: 2017-08-10
Start Page: 234
End Page: 238
Language: English
DOI: 10.1038/nature23291
PROVIDER: scopus
PUBMED: 28783719
PMCID: PMC5648058
Notes: Article -- Export Date: 5 September 2017 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    361 Rosen
  2. David Solit
    431 Solit
  3. Rona Denit Yaeger
    64 Yaeger
  4. Barry Stephen Taylor
    138 Taylor
  5. Zhan Yao
    22 Yao
  6. Linde Anne Miles
    6 Miles
  7. Matthew   Chang
    21 Chang
  8. Neilawattie Merna Torres
    14 Torres
  9. HuiYong   Zhao
    6 Zhao