title: Hedgehog fights back: mechanisms of acquired resistance against Smoothened antagonists.
abstract: Acquired resistance to targeted therapies threatens the value of these otherwise very promising agents. The recent description of resistance to the Hedgehog pathway inhibitor vismodegib (GDC-0449) in a medulloblastoma patient who had a dramatic initial response has spurred efforts to understand potential mechanisms of drug resistance. Elucidating these mechanisms will play a significant role in informing strategies to overcome this meaningful limitation.
authors.affiliation: Department of Molecular Biology, Genentech Inc., South San Francisco, CA, USA.
authors.forename: Ciara
authors.initials: C
authors.lastname: Metcalfe
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000813:Anilides / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001478:Basal Cell Nevus Syndrome / Q000235:genetics; D001713:Biphenyl Compounds / Q000627:therapeutic use; D002280:Basal Cell Carcinoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000502:physiology*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology; D000072079:Patched Receptors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics / Q000502:physiology; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D012878:Skin Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D000072086:Smoothened Receptor; D023041:Xenograft Model Antitumor Assays
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D053823:Hedgehog Proteins; C538724:HhAntag691; D009363:Neoplasm Proteins; D000072079:Patched Receptors; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; D000072086:Smoothened Receptor; C561435:sonidegib