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.
Heidorn
Sonja J
SJ
The Institute of Cancer Research, Signal Transduction Team, Section of Cell and Molecular Biology, 237 Fulham Road, London SW3 6JB, UK.
Milagre
Carla
C
Whittaker
Steven
S
Nourry
Arnaud
A
Niculescu-Duvas
Ion
I
Dhomen
Nathalie
N
Hussain
Jahan
J
Reis-Filho
Jorge S
JS
Springer
Caroline J
CJ
Pritchard
Catrin
C
Marais
Richard
R
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