Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.
Cell
; 140(2): 209-21, 2010 Jan 22.
Article
em 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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas ras
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Proteínas Proto-Oncogênicas c-raf
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Proteínas Proto-Oncogênicas B-raf
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Melanoma
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Antineoplásicos
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Ano de publicação:
2010
Tipo de documento:
Article