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Anticancer drugs

RAF complexities spark caution

Nature Reviews Drug Discovery volume 9, page 271 (2010)Cite this article

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Although ATP-competitive RAF inhibitors are active against tumours with mutant, constitutively active BRAF(V600E), which generally do not harbour activating RAS mutations, they do not suppress the growth of tumours with mutant RAS or wild-type BRAF. Indeed, RAF inhibitors can activate RAF signalling pathways in some cells. The RAS–RAF pathway is not linear and involves interactions between several kinases. BRAF can bind and activate CRAF in a RAS-dependent manner, leading to the activation of the downstream kinases MEK and ERK. Most oncogenic mutants of BRAF activate MEK directly; however, some act through CRAF and occasionally BRAF mutants that have no kinase activity are selected for in human tumours.

Richard Marais and colleagues found that drugs that inhibit BRAF result in the binding of BRAF to CRAF and CRAF activation in the presence of activated wild-type or oncogenic RAS. A gatekeeper mutant of BRAF that is much less sensitive to RAF inhibitors could not dimerize with CRAF, but expression of a CRAF gatekeeper mutant did not prevent binding to BRAF or MEK–ERK activation in the presence of a RAF inhibitor. Use of a kinase-dead mutant of BRAF showed that the kinase activity of BRAF was not needed for BRAF to dimerize with CRAF and activate it. These results indicate that BRAF inhibitors can activate the MEK–ERK pathway because they induce a kinase-dead BRAF, which — by a mechanism that involves activated RAS — dimerizes with and induces activation of CRAF. These authors showed that kinase-dead BRAF can cooperate with oncogenic KRAS to induce melanoma in mice, further illustrating the complexities of this pathway.

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ORIGINAL RESEARCH PAPERS

  1. Heidorn, S. J. et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumour progression through CRAF. Cell 140, 209–221 (2010)

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  2. Poulikakos, P. I., Zhang, C., Bollag, G., Shokat, K. M. & Rosen, N. RAF inhibitors transactivate RAF dimers and ERK signalling in cells with wild-type BRAF. Nature 23 Feb 2010 (doi:10.1038/nature08902)

    Article  CAS  Google Scholar 

  3. Hatzivassiliou, G. et al. RAF inhibitors prime wild-type RAF to activate the MAPK pathway and enhance growth. Nature 3 Feb 2010 (doi:10.10.38/nature08833)

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  1. Nature Reviews Cancer,

    Nicola McCarthy

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  1. Nicola McCarthy
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McCarthy, N. RAF complexities spark caution. Nat Rev Drug Discov 9, 271 (2010). https://doi.org/10.1038/nrd3153

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  • DOI: https://doi.org/10.1038/nrd3153

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