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Title: Kinase-dead BRAF and oncongenic RAS cooperate to drive tumour progression through CRAF
Authors: Heidorn, S. J.
Milagre, C.
Whittaker, S.
Nourry, A.
Niculescu Duvas, I.
Dhomen, I.
Hussain, Jahan
Reis Filho, J. S.
Springer, C. J.
Pritchard, Catrin
Marais, R.
First Published: 21-Jan-2010
Publisher: Elsevier (Cell Press)
Citation: Cell, 2010, 140 (2), pp. 209-221
Abstract: 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.
DOI Link: 10.1016/j.cell.2009.12.040
ISSN: 0092-8674
eISSN: 1097-4172
Version: Publisher Version
Status: Peer-reviewed
Type: Journal Article
Rights: Open access under CC BY license
Description: Supplemental Information includes Extended Experimental Procedures, four figures, and three tables and can be found with this article online at doi: 10.1016/j.cell.2009.12.040.
Appears in Collections:Published Articles, Dept. of Cancer Studies and Molecular Medicine

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