title: Smoothened (SMO) receptor mutations dictate resistance to vismodegib in basal cell carcinoma.
abstract: Basal cell carcinomas (BCCs) and a subset of medulloblastomas are characterized by loss-of-function mutations in the tumor suppressor gene, PTCH1. PTCH1 normally functions by repressing the activity of the Smoothened (SMO) receptor. Inactivating PTCH1 mutations result in constitutive Hedgehog pathway activity through uncontrolled SMO signaling. Targeting this pathway with vismodegib, a novel SMO inhibitor, results in impressive tumor regression in patients harboring genetic defects in this pathway. However, a secondary mutation in SMO has been reported in medulloblastoma patients following relapse on vismodegib to date. This mutation preserves pathway activity, but appears to confer resistance by interfering with drug binding. Here we report for the first time on the molecular mechanisms of resistance to vismodegib in two BCC cases. The first case, showing progression after 2 months of continuous vismodegib (primary resistance), exhibited the new SMO G497W mutation. The second case, showing a complete clinical response after 5 months of treatment and a subsequent progression after 11 months on vismodegib (secondary resistance), exhibited a PTCH1 nonsense mutation in both the pre- and the post-treatment specimens, and the SMO D473Y mutation in the post-treatment specimens only. In silico analysis demonstrated that SMO(G497W) undergoes a conformational rearrangement resulting in a partial obstruction of the protein drug entry site, whereas the SMO D473Y mutation induces a direct effect on the binding site geometry leading to a total disruption of a stabilizing hydrogen bond network. Thus, the G497W and D473Y SMO mutations may represent two different mechanisms leading to primary and secondary resistance to vismodegib, respectively.
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy. Electronic address: sabrina.pricl@di3.units.it.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cortelazzi
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Dal Col
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Domenico
authors.initials: D
authors.lastname: Marson
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, University of Trieste, Piazzale Europa 1, 34127 Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fermeglia
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy.
authors.forename: Lisa
authors.initials: L
authors.lastname: Licitra
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy.
authors.forename: Silvana
authors.initials: S
authors.lastname: Pilotti
authors.affiliation: Head and Neck Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bossi
authors.affiliation: Laboratory of Experimental Molecular Pathology, Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133 Milan, Italy. Electronic address: federica.perrone@istitutotumori.mi.it.
authors.forename: Federica
authors.initials: F
authors.lastname: Perrone
mesh_terms: D019943:Amino Acid Substitution; D000813:Anilides / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011725:Pyridines / Q000494:pharmacology*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D000072086:Smoothened Receptor
chemical_list: D000813:Anilides; C538724:HhAntag691; D009363:Neoplasm Proteins; C000606236:PTCH1 protein, human; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor
keywords: Basal cell carcinoma; Hedgehog pathway; PTCH1; Primary resistance; SMO; Secondary resistance; Vismodegib