Effects of oncogenic mutations in Smoothened and Patched can be reversed by cyclopamine

Basal cell carcinoma, medulloblastoma, rhabdomyosarcoma and other human tum ours are associated with mutations that activate the proto-oncogene Smoothe ned (SMO) or that inactivate the tumour suppressor Patched (PTCH). Smoothen ed and Patched mediate the cellular response to the Hedgehog (Hh) secreted protein signal, and oncogenic mutations affecting these proteins cause exce ss activity of the Hh response pathway(1,2). Here we show that the plant-de rived teratogen cyclopamine, which inhibits the Hh response(3,4), is a pote ntial 'mechanism-based' therapeutic agent for treatment of these tumours. W e show that cyclopamine or synthetic derivatives with improved potency bloc k activation of the Hh response pathway and abnormal cell growth associated with both types of oncogenic mutation. Our results also indicate that cycl opamine may act by influencing the balance between active and inactive form s of Smoothened.