期刊
NATURE
卷 548, 期 7666, 页码 234-+出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nature23291
关键词
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资金
- National Institutes of Health (NIH) [P01 CA129243, R35 CA210085]
- Melanoma Research Alliance [237059, 348724]
- Commonwealth Foundation for Cancer Research
- Center for Experimental Therapeutics at Memorial Sloan Kettering Cancer Center
- Stand Up To Cancer - American Cancer Society Lung Cancer Dream Team Translational Research Grant [SU2C-AACR-DT17-15]
- NIH MSKCC Cancer Center Support Grant [P30 CA008748]
- Conquer Cancer Foundation of the American Society of Clinical Oncology
- NIH [R01 CA204749, R01 CA180037, U54 ODSS020355, T32 GM007175]
- Sontag Foundation
- Josie Robertson Foundation
- Cycle For Survival
- Arlene and Joseph Taub Foundation
- European Research Council [ERC-AG/250297-RAS AHEAD]
- EU [HEALTH-F2-2010-259770/LUNGTARGET, HEALTH-2010-260791/ EUROCANPLATFORM]
- Spanish Ministry of Economy and Competitiveness [SAF2011-30173, SAF2014-59864-R]
- AXA Research Fund
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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