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B-RAF is a therapeutic target in melanoma

Oncogene volume 23, pages 6292–6298 (2004)Cite this article

Abstract

B-RAF is a serine/threonine-specific protein kinase that is mutated in approximately 70% of human melanomas. However, the role of this signalling molecule in cancer is unclear. Here, we show that ERK is constitutively activated in melanoma cells expressing oncogenic B-RAF and that this activity is required for proliferation. B-RAF depletion by siRNA blocks ERK activity, whereas A-RAF and C-RAF depletion do not affect ERK signalling. B-RAF depletion inhibits DNA synthesis and induces apoptosis in three melanoma cell lines and we show that the RAF inhibitor BAY43-9006 also blocks ERK activity, inhibits DNA synthesis and induces cell death in these cells. BAY43-9006 targets B-RAF signalling in vivo and induces a substantial growth delay in melanoma tumour xenografts. Our data demonstrate that oncogenic B-RAF activates ERK signalling, induces proliferation and protects cells from apoptosis, demonstrating that it is an important therapeutic target and thus provides novel strategies for clinical management of melanoma and other cancers.

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Acknowledgements

We thank Ian Titley for technical instruction with FACS analysis and Hugh Paterson and David Robertson for instruction and support with the imaging facilities. We also thank the members of the Signal Transduction Team for helpful discussions. This work is funded by Cancer Research UK and the Biotechnology and Biological Sciences Research Council (Grant number 353/C14718).

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Author notes

  1. Antonio Chiloeches

    Present address: Departamento de Bioquimica y Biologia Molecular, Campus Universitario-Facultad de Medicina, Ctra. de Barcelona, Km.33.600, 28871, Alcala de Henares, Madrid, Spain

Authors and Affiliations

  1. Signal Transduction Team, The Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Maria Karasarides, Antonio Chiloeches, Robert Hayward & Richard Marais

  2. Gene and Oncogene Targeting Team, The Institute of Cancer Research, 15 Cotswold Road, Sutton, SM2 5NG, Surrey, UK

    Dan Niculescu-Duvaz, Ian Scanlon, Frank Friedlos, Lesley Ogilvie, Douglas Hedley, Jan Martin & Caroline J Springer

  3. Oncogene Team, The Cancer Research UK Centre for Cell and Molecular Biology, The Institute of Cancer Research, 237 Fulham Road, London, SW3 6JB, UK

    Christopher J Marshall

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Correspondence to Richard Marais.

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Karasarides, M., Chiloeches, A., Hayward, R. et al. B-RAF is a therapeutic target in melanoma. Oncogene 23, 6292–6298 (2004). https://doi.org/10.1038/sj.onc.1207785

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