Cancer Cell
Volume 23, Issue 1, 14 January 2013, Pages 23-34
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Article
Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists

https://doi.org/10.1016/j.ccr.2012.11.017Get rights and content
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Summary

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.

Highlights

► Itraconazole inhibits the activity of GDC-0449-resistant SMOD477G ► Itraconazole and ATO combine to block SMOD477G pathway activity in vitro ► Itraconazole and ATO inhibit SMOWT and SMOD477G tumor growth and prolong survival ► Itraconazole and ATO retain activity in all reported drug-resistant SMO mutants

Cited by (0)

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These authors contributed equally to this work

11

Present address: Division of Hematology-Oncology, Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern, Dallas, TX 75390-8593, USA

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Present address: Helen Diller Comprehensive Cancer Center, University of California at San Francisco, San Francisco, CA 94158, USA