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.
Pubmed ID: 20141835 RIS Download
Animals | Antineoplastic Agents | Cell Line, Tumor | Humans | Melanoma | Mice | Mice, Transgenic | Proto-Oncogene Proteins B-raf | Proto-Oncogene Proteins c-raf | ras Proteins