Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma

Baozhi Chen, Vinh Trang, Alex Lee, Noelle S. Williams, Alexandra N. Wilson, Ervin H. Epstein, Jean Y. Tang, James Kim

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

Deregulation of Hedgehog (Hh) pathway signaling has been associated with the pathogenesis of various malignancies, including basal cell carcinomas (BCC). Inhibitors of the Hh pathway currently available or under clinical investigation all bind and antagonize Smoothened (SMO), inducing a marked but transient clinical response. Tumor regrowth and therapy failure were attributed to mutations in the binding site of these small-molecule SMO antagonists. The antifungal itraconazole was demonstrated to be a potent SMO antagonist with a distinct mechanism of action from that of current SMO inhibitors. However, itraconazole represents a suboptimal therapeutic option due to its numerous drug-drug interactions. Here, we show that posaconazole, a second-generation triazole antifungal with minimal drug-drug interactions and a favorable side-effect profile, is also a potent inhibitor of the Hh pathway that functions at the level of SMO. We demonstrate that posaconazole inhibits the Hh pathway by a mechanism distinct from that of cyclopamine and other cyclopamine-competitive SMO antagonists but, similar to itraconazole, has robust activity against drug-resistant SMO mutants and inhibits the growth of Hh-dependent BCC in vivo. Our results suggest that posaconazole, alone or in combination with other Hh pathway antagonists, may be readily tested in clinical studies for the treatment of Hh-dependent cancers.

Original languageEnglish (US)
Pages (from-to)866-876
Number of pages11
JournalMolecular Cancer Therapeutics
Volume15
Issue number5
DOIs
StatePublished - May 1 2016

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Triazoles
Itraconazole
Basal Cell Carcinoma
Drug Interactions
Pharmaceutical Preparations
Neoplasms
Binding Sites
Mutation
Therapeutics
Growth
posaconazole
cyclopamine

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma. / Chen, Baozhi; Trang, Vinh; Lee, Alex; Williams, Noelle S.; Wilson, Alexandra N.; Epstein, Ervin H.; Tang, Jean Y.; Kim, James.

In: Molecular Cancer Therapeutics, Vol. 15, No. 5, 01.05.2016, p. 866-876.

Research output: Contribution to journalArticle

Chen, Baozhi ; Trang, Vinh ; Lee, Alex ; Williams, Noelle S. ; Wilson, Alexandra N. ; Epstein, Ervin H. ; Tang, Jean Y. ; Kim, James. / Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma. In: Molecular Cancer Therapeutics. 2016 ; Vol. 15, No. 5. pp. 866-876.
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