Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tumours are associated with mutations that activate the proto-oncogene Smoothened (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothened and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause excess activity of the Hh response pathway1,2. Here we show that the plant-derived teratogen cyclopamine, which inhibits the Hh response3,4, is a potential ‘mechanism-based’ therapeutic agent for treatment of these tumours. We show that cyclopamine or synthetic derivatives with improved potency block activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cyclopamine may act by influencing the balance between active and inactive forms of Smoothened.
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We thank P. A. Cole, D. Leahy, J. Nathans, R. Reed and G. Seydoux for critical review of the manuscript, W. Gaffield for Veratrum extracts and K. Young for technical assistance. J.T. was supported by the Finnish Academy and the European Molecular Biology Organization. J.K.C. is a recipient of a postdoctoral fellowship from the Damon Runyon-Walter Winchell Cancer Research Fund and M.K.C. was supported by a postdoctoral fellowship from the Howard Hughes Medical Institute and a career development award from the Burroughs Wellcome Fund. P.A.B. and M.P.S. are investigators of the Howard Hughes Medical Institute.
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Taipale, J., Chen, J., Cooper, M. et al. Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine. Nature 406, 1005–1009 (2000). https://doi.org/10.1038/35023008
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