Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists

James Kim, Blake T. Aftab, Jean Y. Tang, Daniel Kim, Alex H. Lee, Melika Rezaee, Jynho Kim, Baozhi Chen, Emily M. King, Alexandra Borodovsky, Gregory J. Riggins, Ervin H. Epstein, Philip A. Beachy, Charles M. Rudin

Research output: Contribution to journalArticle

224 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)23-34
Number of pages12
JournalCancer Cell
Volume23
Issue number1
DOIs
StatePublished - Jan 14 2013

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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    Kim, J., Aftab, B. T., Tang, J. Y., Kim, D., Lee, A. H., Rezaee, M., Kim, J., Chen, B., King, E. M., Borodovsky, A., Riggins, G. J., Epstein, E. H., Beachy, P. A., & Rudin, C. M. (2013). Itraconazole and Arsenic Trioxide Inhibit Hedgehog Pathway Activation and Tumor Growth Associated with Acquired Resistance to Smoothened Antagonists. Cancer Cell, 23(1), 23-34. https://doi.org/10.1016/j.ccr.2012.11.017