Journal
CELL
Volume 140, Issue 2, Pages 209-221Publisher
CELL PRESS
DOI: 10.1016/j.cell.2009.12.040
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Funding
- Institute of Cancer Research, Cancer Research UK [C107/A10433]
- Wellcome Trust [080333/Z/06/Z]
- Breakthrough Breast Cancer
- NHS
- Wellcome Trust [080333/Z/06/Z] Funding Source: Wellcome Trust
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We describe a mechanism of tumorigenesis mediated by kinase-dead BRAF in the presence of oncogenic RAS. We show that drugs that selectively inhibit BRAF drive RAS-dependent BRAF binding to CRAF, CRAF activation, and MEK-ERK signaling. This does not occur when oncogenic BRAF is inhibited, demonstrating that BRAF inhibition per se does not drive pathway activation; it only occurs when BRAF is inhibited in the presence of oncogenic RAS. Kinase-dead BRAF mimics the effects of the BRAF-selective drugs and kinase-dead Braf and oncogenic Ras cooperate to induce melanoma in mice. Our data reveal another paradigm of BRAF-mediated signaling that promotes tumor progression. They highlight the importance of understanding pathway signaling in clinical practice and of genotyping tumors prior to administering BRAF-selective drugs, to identify patients who are likely to respond and also to identify patients who may experience adverse effects.
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