Kinase-dead BRAF and Oncogenic RAS Cooperate to Drive Tumor Progression Through CRAF

Cell. 2010 Jan 22;140(2):209-21. doi: 10.1016/j.cell.2009.12.040.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / adverse effects*
  • Cell Line, Tumor
  • Humans
  • Melanoma / drug therapy*
  • Mice
  • Mice, Transgenic
  • Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism*
  • ras Proteins / metabolism*

Substances

  • Antineoplastic Agents
  • Proto-Oncogene Proteins B-raf
  • Proto-Oncogene Proteins c-raf
  • ras Proteins