Citation

  • Authors: Heidorn, S. J., Milagre, C., Whittaker, S., Nourry, A., Niculescu-Duvas, I., Dhomen, N., Hussain, J., Reis-Filho, J. S., Springer, C. J., Pritchard, C., Marais, R.
  • Year: 2010
  • Journal: Cell 140 209-21
  • Applications: in vitro / siRNA / INTERFERin
  • Cell types:
    1. Name: A375
      Description: Human skin melanoma cells
      Known as: A-375
    2. Name: DO4
    3. Name: HCT 116
      Description: Human colon carcinoma cells
      Known as: HCT116
    4. Name: MM415
    5. Name: MM485
    6. Name: PMWK
    7. Name: SW620
      Description: Human colon adenocarcinoma cells
    8. Name: WM1791c
      Description: Human skin melanoma cells
    9. Name: WM852

Method

5nM siRNA

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.

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