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RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF

Author

Listed:
  • Poulikos I. Poulikakos

    (Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA)

  • Chao Zhang

    (University of California San Francisco, California 94158, USA)

  • Gideon Bollag

    (Plexxikon Inc., 91 Bolivar Drive, Berkeley, California 94710, USA)

  • Kevan M. Shokat

    (University of California San Francisco, California 94158, USA)

  • Neal Rosen

    (Memorial Sloan-Kettering Cancer Center, New York, New York 10065, 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

  • Poulikos I. Poulikakos & Chao Zhang & Gideon Bollag & Kevan M. Shokat & Neal Rosen, 2010. "RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF," Nature, Nature, vol. 464(7287), pages 427-430, March.
    • Handle: RePEc:nat:nature:v:464:y:2010:i:7287:d:10.1038_nature08902
    DOI: 10.1038/nature08902
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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. Cang Li & Zhengyu Wang & Licheng Yao & Xingyu Lin & Yongping Jian & Yujia Li & Jie Zhang & Jingwei Shao & Phuc D. Tran & James R. Hagman & Meng Cao & Yusheng Cong & Hong-yu Li & Colin R. Goding & Zhi-, 2024. "Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    4. 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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