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

Poulikos I. Poulikakos, Chao Zhang, Gideon Bollag, Kevan M. Shokat and Neal Rosen ()
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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

Nature, 2010, vol. 464, issue 7287, 427-430

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/nature08902

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