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Recognition of the multiple roles of Hedgehog signaling in cancer has prompted intensive efforts to develop targeted pathway inhibitors. Leading inhibitors in clinical development act by binding to a common site within Smoothened, a critical pathway component. Acquired Smoothened mutations, including SMOD477G, confer resistance to these inhibitors. Here, we report that itraconazole and arsenic trioxide, two agents in clinical use that inhibit Hedgehog signaling by mechanisms distinct from that of current Smoothened antagonists, retain inhibitory activity in vitro in the context of all reported resistance-conferring Smoothened mutants and GLI2 overexpression. Itraconazole and arsenic trioxide, alone or in combination, inhibit the growth of medulloblastoma and basal cell carcinoma in vivo, and prolong survival of mice with intracranial drug-resistant SMOD477G medulloblastoma. ⺠Itraconazole inhibits the activity of GDC-0449-resistant SMOD477G ⺠Itraconazole and ATO combine to block SMOD477G pathway activity in vitro ⺠Itraconazole and ATO inhibit SMOWT and SMOD477G tumor growth and prolong survival ⺠Itraconazole and ATO retain activity in all reported drug-resistant SMO mutants
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