title: Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma.
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. Mol Cancer Ther; 15(5); 866-76. ©2016 AACR.
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern, Dallas, Texas.
authors.forename: Baozhi
authors.initials: B
authors.lastname: Chen
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas.
authors.forename: Vinh
authors.initials: V
authors.lastname: Trang
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California.
authors.forename: Alex
authors.initials: A
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, University of Texas Southwestern, Dallas, Texas.
authors.forename: Noelle S
authors.initials: NS
authors.lastname: Williams
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern, Dallas, Texas.
authors.forename: Alexandra N
authors.initials: AN
authors.lastname: Wilson
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California.
authors.forename: Ervin H
authors.initials: EH
authors.lastname: Epstein
authors.affiliation: Children's Hospital Oakland Research Institute, Oakland, California. Department of Dermatology, Stanford University, Stanford, California.
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.affiliation: Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern, Dallas, Texas. Department of Internal Medicine, University of Texas Southwestern, Dallas, Texas. James.Kim@UTSouthwestern.edu.
authors.forename: James
authors.initials: J
authors.lastname: Kim
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D053823:Hedgehog Proteins / Q000378:metabolism*; D006801:Humans; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D000072086:Smoothened Receptor / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000935:Antifungal Agents; D000970:Antineoplastic Agents; D053823:Hedgehog Proteins; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014230:Triazoles; C101425:posaconazole
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