Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.
Cell
; 140(2): 209-21, 2010 Jan 22.
Article
in En
| MEDLINE
| ID: mdl-20141835
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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Ras Proteins
/
Proto-Oncogene Proteins c-raf
/
Proto-Oncogene Proteins B-raf
/
Melanoma
/
Antineoplastic Agents
Limits:
Animals
/
Humans
Language:
En
Journal:
Cell
Year:
2010
Type:
Article
Affiliation country:
United kingdom