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RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth

Author

Listed:
  • Georgia Hatzivassiliou

    (Genentech, South San Francisco, California 94080, USA)

  • Kyung Song

    (Genentech, South San Francisco, California 94080, USA)

  • Ivana Yen

    (Genentech, South San Francisco, California 94080, USA)

  • Barbara J. Brandhuber

    (Array BioPharma, Boulder, Colorado 80301, USA)

  • Daniel J. Anderson

    (Genentech, South San Francisco, California 94080, USA)

  • Ryan Alvarado

    (Genentech, South San Francisco, California 94080, USA)

  • Mary J. C. Ludlam

    (Genentech, South San Francisco, California 94080, USA)

  • David Stokoe

    (Genentech, South San Francisco, California 94080, USA)

  • Susan L. Gloor

    (Array BioPharma, Boulder, Colorado 80301, USA)

  • Guy Vigers

    (Array BioPharma, Boulder, Colorado 80301, USA)

  • Tony Morales

    (Array BioPharma, Boulder, Colorado 80301, USA)

  • Ignacio Aliagas

    (Genentech, South San Francisco, California 94080, USA)

  • Bonnie Liu

    (Genentech, South San Francisco, California 94080, USA)

  • Steve Sideris

    (Genentech, South San Francisco, California 94080, USA)

  • Klaus P. Hoeflich

    (Genentech, South San Francisco, California 94080, USA)

  • Bijay S. Jaiswal

    (Genentech, South San Francisco, California 94080, USA)

  • Somasekar Seshagiri

    (Genentech, South San Francisco, California 94080, USA)

  • Hartmut Koeppen

    (Genentech, South San Francisco, California 94080, USA)

  • Marcia Belvin

    (Genentech, South San Francisco, California 94080, USA)

  • Lori S. Friedman

    (Genentech, South San Francisco, California 94080, USA)

  • Shiva Malek

    (Genentech, South San Francisco, California 94080, USA)

Abstract

Mixed signals from RAF Abnormal activation of the RAS-RAF-MEK-ERK signalling pathway is a feature of many human cancers, making it an attractive target for antitumour therapy. Several RAF and MEK inhibitors are in clinical trials, but an unexpected complication has emerged. Although selective BRAF inhibitors are effective in treating mutant BRAF melanoma, in which they potently suppress RAF-MEK-ERK signalling, the same inhibitors are ineffective against tumours that carry an oncogenic mutation in the KRAS gene. Two groups now report that the reason for this dramatic difference is that RAF 'inhibitors' have dual activity, functioning as either inhibitors or activators of RAF, depending on the cellular context and mutational status of RAF. In News & Views, Karen Cichowski and Pasi Jänne discuss the mechanistic and clinical implications of these findings and similar work reported in Cell.

Suggested Citation

  • Georgia Hatzivassiliou & Kyung Song & Ivana Yen & Barbara J. Brandhuber & Daniel J. Anderson & Ryan Alvarado & Mary J. C. Ludlam & David Stokoe & Susan L. Gloor & Guy Vigers & Tony Morales & Ignacio A, 2010. "RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth," Nature, Nature, vol. 464(7287), pages 431-435, March.
    • Handle: RePEc:nat:nature:v:464:y:2010:i:7287:d:10.1038_nature08833
    DOI: 10.1038/nature08833
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    Cited by:

    1. Maria Szaruga & Dino A. Janssen & Claudia Miguel & George Hodgson & Agnieszka Fatalska & Aleksandra P. Pitera & Antonina Andreeva & Anne Bertolotti, 2023. "Activation of the integrated stress response by inhibitors of its kinases," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Peter Rashkov & Ian P Barrett & Robert E Beardmore & Claus Bendtsen & Ivana Gudelj, 2016. "Kinase Inhibition Leads to Hormesis in a Dual Phosphorylation-Dephosphorylation Cycle," PLOS Computational Biology, Public Library of Science, vol. 12(11), pages 1-15, November.
    3. Revati Darp & Marc A. Vittoria & Neil J. Ganem & Craig J. Ceol, 2022. "Oncogenic BRAF induces whole-genome doubling through suppression of cytokinesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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