Reference Detail

Ref Type Journal Article
PMID (26823493)
Authors Chen B, Trang V, Lee A, Williams NS, Wilson AN, Epstein EH, Tang JY, Kim J
Title Posaconazole, a Second-Generation Triazole Antifungal Drug, Inhibits the Hedgehog Signaling Pathway and Progression of Basal Cell Carcinoma.
Journal Molecular cancer therapeutics
Vol 15
Issue 5
Date 2016 May
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
SMO N219D Advanced Solid Tumor sensitive Posaconazole Preclinical Actionable In a preclinical study, Posaconazole inhibited Hedghog signaling in mouse fibroblasts over expressing murine SMO N223D (corresponding to human SMO N219D) in culture (PMID: 26823493). 26823493
SMO E518K Advanced Solid Tumor sensitive Arsenic trioxide + Posaconazole Preclinical Actionable In a preclinical study, combination of Posaconazole and Trisenox (Arsenic trioxide) demonstrated enhanced inhibition of Hedghog signaling in mouse fibroblasts over expressing murine SMO E522K (corresponding to human SMO E518K) in culture (PMID: 26823493). 26823493
SMO W535L Advanced Solid Tumor resistant Posaconazole Preclinical Actionable In a preclinical study, Posaconazole did not inhibit Hedghog signaling in mouse fibroblasts over expressing murine SMO W539L (corresponding to human SMO W535L) in culture (PMID: 26823493). 26823493
SMO E518K Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO E522K (corresponding to human SMO E518K) were resistant to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO D384N Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO D388N (corresponding to human SMO D384N) were resistant to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO E518K Advanced Solid Tumor decreased response Sonidegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO E522K (corresponding to human SMO E518K) demonstrated decreased response to Odomzo (sonidegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO N219D Advanced Solid Tumor sensitive Arsenic trioxide + Posaconazole Preclinical Actionable In a preclinical study, combination of Posaconazole and Trisenox (Arsenic trioxide) demonstrated enhanced inhibition of Hedghog signaling in mouse fibroblasts over expressing murine SMO N223D (corresponding to human SMO N219D) in culture (PMID: 26823493). 26823493
SMO D473G Advanced Solid Tumor sensitive Arsenic trioxide + Posaconazole Preclinical Actionable In a preclinical study, combination of Posaconazole and Trisenox (Arsenic trioxide) demonstrated enhanced inhibition of Hedghog signaling in mouse fibroblasts over expressing murine SMO D477G (corresponding to human SMO D473G) in culture (PMID: 26823493). 26823493
SMO S387N Advanced Solid Tumor sensitive Posaconazole Preclinical Actionable In a preclinical study, Posaconazole inhibited Hedghog signaling in mouse fibroblasts over expressing murine SMO S391N (corresponding to human SMO S387N) in culture (PMID: 26823493). 26823493
SMO N219D Advanced Solid Tumor resistant Sonidegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO N223D (corresponding to human SMO N219D) were resistant to Odomzo (sonidegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO D384N Advanced Solid Tumor resistant Sonidegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO D388N (corresponding to human SMO D384N) were resistant to Odomzo (sonidegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO E518K Advanced Solid Tumor sensitive Posaconazole Preclinical Actionable In a preclinical study, Posaconazole inhibited Hedghog signaling in mouse fibroblasts over expressing murine SMO E522K (corresponding to human SMO E518K) in culture (PMID: 26823493). 26823493
SMO S387N Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO S391N (corresponding to human SMO S387N) were resistant to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO D384N Advanced Solid Tumor sensitive Posaconazole Preclinical Actionable In a preclinical study, Posaconazole inhibited Hedghog signaling in mouse fibroblasts over expressing murine SMO D388N (corresponding to human SMO D384N) in culture (PMID: 26823493). 26823493
SMO S387N Advanced Solid Tumor sensitive Arsenic trioxide + Posaconazole Preclinical Actionable In a preclinical study, combination of Posaconazole and Trisenox (Arsenic trioxide) demonstrated enhanced inhibition of Hedghog signaling in mouse fibroblasts over expressing murine SMO S391N (corresponding to human SMO S387N) in culture (PMID: 26823493). 26823493
SMO S387N Advanced Solid Tumor resistant Sonidegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO S391N (corresponding to human SMO S387N) were resistant to Odomzo (sonidegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493
SMO D473G Advanced Solid Tumor sensitive Posaconazole Preclinical Actionable In a preclinical study, Posaconazole inhibited Hedghog signaling in mouse fibroblasts over expressing murine SMO D477G (corresponding to human SMO D473G) in culture (PMID: 26823493). 26823493
SMO D384N Advanced Solid Tumor sensitive Arsenic trioxide + Posaconazole Preclinical Actionable In a preclinical study, combination of Posaconazole and Trisenox (Arsenic trioxide) demonstrated enhanced inhibition of Hedghog signaling in mouse fibroblasts over expressing murine SMO D388N (corresponding to human SMO D384N) in culture (PMID: 26823493). 26823493
SMO D473G Advanced Solid Tumor resistant Vismodegib Preclinical Actionable In a preclinical study, transformed mouse fibroblast cells over expressing murine SMO D477G (corresponding to human SMO D473G) were resistant to Erivedge (vismodegib) induced Hedgehog pathway inhibition in cell culture (PMID: 26823493). 26823493