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)1. 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.
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We are grateful to P. Lito, Y. Gao, W. Su, L. Desrochers, D. Santamaria and O. Abdel-Wahab for useful discussions. We thank S. Lowe for the vectors of the retrovirus-based inducible expression system and M. Baccarini for the Raf1-knockout MEFs. We thank Novartis for supplying INC280. We also thank I. Maruani Ryan for her help on this work. This research was supported by grants to N.R. from the National Institutes of Health (NIH) (P01 CA129243; R35 CA210085); the Melanoma Research Alliance (237059 and 348724); The Commonwealth Foundation for Cancer Research and The Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center; and the Stand Up To Cancer – American Cancer Society Lung Cancer Dream Team Translational Research Grant (SU2C-AACR-DT17-15). Support was also received from the NIH MSKCC Cancer Center Support Grant P30 CA008748. Additional funding was provided by a Career Development Award from the Conquer Cancer Foundation of the American Society of Clinical Oncology (R.Y.); and from the NIH (R01 CA204749 and R01 CA180037), the Sontag and Josie Robertson Foundations and the Cycle For Survival (B.S.T.). Additional NIH funding was received by E.d.S. (U54 ODSS020355). We would like to acknowledge the support of the Arlene and Joseph Taub Foundation and of Paula and Thomas McInerney, without which this work would not have been possible. M.T.C. was supported in part by the NIH training grant T32 GM007175. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. This work was also supported by grants from the European Research Council (ERC-AG/250297-RAS AHEAD), EU-Framework Programme (HEALTH-F2-2010-259770/LUNGTARGET and HEALTH-2010-260791/EUROCANPLATFORM) and Spanish Ministry of Economy and Competitiveness (SAF2011-30173 and SAF2014-59864-R) to M.B. M.B. is the recipient of an Endowed Chair from the AXA Research Fund.
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International Journal of Cancer (2019)