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

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 Aliagas, Bonnie Liu, Steve Sideris, Klaus P. Hoeflich, Bijay S. Jaiswal, Somasekar Seshagiri, Hartmut Koeppen, Marcia Belvin, Lori S. Friedman and Shiva Malek ()
Additional contact information
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

Nature, 2010, vol. 464, issue 7287, 431-435

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.

Date: 2010
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DOI: 10.1038/nature08833

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