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Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF.

Cell | Jan 22, 2010

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

Mesh terms: Animals | Antineoplastic Agents | Cell Line, Tumor | Humans | Melanoma | Mice | Mice, Transgenic | Proto-Oncogene Proteins B-raf | Proto-Oncogene Proteins c-raf | ras Proteins

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Associated grants

  • Agency: Cancer Research UK, Id: 13083
  • Agency: Wellcome Trust, Id: 080333/Z/06/Z
  • Agency: Cancer Research UK, Id: C107/A10433

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COSMIC - Catalogue Of Somatic Mutations In Cancer

Database to store and display somatic mutation information and related details and contains information relating to human cancers. The mutation data and associated information is extracted from the primary literature. In order to provide a consistent view of the data a histology and tissue ontology has been created and all mutations are mapped to a single version of each gene. The data can be queried by tissue, histology or gene and displayed as a graph, as a table or exported in various formats.
Some key features of COSMIC are:
* Contains information on publications, samples and mutations. Includes samples which have been found to be negative for mutations during screening therefore enabling frequency data to be calculated for mutations in different genes in different cancer types.
* Samples entered include benign neoplasms and other benign proliferations, in situ and invasive tumours, recurrences, metastases and cancer cell lines.


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