title: Itraconazole and arsenic trioxide inhibit Hedgehog pathway activation and tumor growth associated with acquired resistance to smoothened antagonists.
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 SMO(D477G), 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 SMO(D477G) medulloblastoma.
authors.affiliation: Institute for Stem Cell Biology and Regenerative Medicine, Stanford University, Stanford, CA 94305, USA.
authors.forename: James
authors.initials: J
authors.lastname: Kim
authors.forename: Blake T
authors.initials: BT
authors.lastname: Aftab
authors.forename: Jean Y
authors.initials: JY
authors.lastname: Tang
authors.forename: Daniel
authors.initials: D
authors.lastname: Kim
authors.forename: Alex H
authors.initials: AH
authors.lastname: Lee
authors.forename: Melika
authors.initials: M
authors.lastname: Rezaee
authors.forename: Jynho
authors.initials: J
authors.lastname: Kim
authors.forename: Baozhi
authors.initials: B
authors.lastname: Chen
authors.forename: Emily M
authors.initials: EM
authors.lastname: King
authors.forename: Alexandra
authors.initials: A
authors.lastname: Borodovsky
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Riggins
authors.forename: Ervin H
authors.initials: EH
authors.lastname: Epstein
authors.forename: Philip A
authors.initials: PA
authors.lastname: Beachy
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D002280:Basal Cell Carcinoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000378:metabolism / Q000502:physiology*; D017964:Itraconazole / Q000494:pharmacology / Q000627:therapeutic use*; D008527:Medulloblastoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors; D015398:Signal Transduction / Q000187:drug effects*; D000072086:Smoothened Receptor
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001152:Arsenicals; D053823:Hedgehog Proteins; C538724:HhAntag691; D010087:Oxides; D011725:Pyridines; D043562:Receptors, G-Protein-Coupled; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D017964:Itraconazole; D000077237:Arsenic Trioxide