TY - JOUR
T1 - Posaconazole, a second-generation triazole antifungal drug, inhibits the hedgehog signaling pathway and progression of basal cell carcinoma
AU - Chen, Baozhi
AU - Trang, Vinh
AU - Lee, Alex
AU - Williams, Noelle S.
AU - Wilson, Alexandra N.
AU - Epstein, Ervin H.
AU - Tang, Jean Y.
AU - Kim, James
N1 - Funding Information:
This research was supported in part by grants to N.S. Williams and the Preclinical Pharmacology Core from Cancer Prevention Research Institute of Texas (RP11078-C3) and the UTSW Institute for Innovations in Medical Technology (IIMT), to J.Y. Tang from the Damon Runyon Cancer Research Foundation (Clinical Investigator Award), to E.H. Epstein Jr from NIH (5R01CA163611), and to J. Kim from Free to Breathe (Young Investigator Research Grant), Bonnie J. Addario Lung Cancer Foundation (Young Investigator Award), UT Southwestern-American Cancer Society Institutional Research Grant and UT Southwestern institutional funds.
Publisher Copyright:
© 2016 American Association for Cancer Research.
PY - 2016/5
Y1 - 2016/5
N2 - 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.
AB - 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.
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U2 - 10.1158/1535-7163.MCT-15-0729-T
DO - 10.1158/1535-7163.MCT-15-0729-T
M3 - Article
C2 - 26823493
AN - SCOPUS:84969531810
SN - 1535-7163
VL - 15
SP - 866
EP - 876
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 5
ER -