Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.
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.
The Institute of Cancer Research, Signal Transduction Team, Section of Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
Sonja J
SJ
Heidorn
Carla
C
Milagre
Steven
S
Whittaker
Arnaud
A
Nourry
Ion
I
Niculescu-Duvas
Nathalie
N
Dhomen
Jahan
J
Hussain
Jorge S
JS
Reis-Filho
Caroline J
CJ
Springer
Catrin
C
Pritchard
Richard
R
Marais
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D045744:Cell Line, Tumor; D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
D000970:Antineoplastic Agents; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D018631:ras Proteins