title: Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.
abstract: The Hedgehog (Hh) signaling pathway is inappropriately activated in certain human cancers, including medulloblastoma, an aggressive brain tumor. GDC-0449, a drug that inhibits Hh signaling by targeting the serpentine receptor Smoothened (SMO), has produced promising anti-tumor responses in early clinical studies of cancers driven by mutations in this pathway. To evaluate the mechanism of resistance in a medulloblastoma patient who had relapsed after an initial response to GDC-0449, we determined the mutational status of Hh signaling genes in the tumor after disease progression. We identified an amino acid substitution at a conserved aspartic acid residue of SMO that had no effect on Hh signaling but disrupted the ability of GDC-0449 to bind SMO and suppress this pathway. A mutation altering the same amino acid also arose in a GDC-0449-resistant mouse model of medulloblastoma. These findings show that acquired mutations in a serpentine receptor with features of a G protein-coupled receptor can serve as a mechanism of drug resistance in human cancer.
authors.affiliation: Genentech, South San Francisco, CA 94080, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Yauch
authors.forename: Gerrit J P
authors.initials: GJ
authors.lastname: Dijkgraaf
authors.forename: Bruno
authors.initials: B
authors.lastname: Alicke
authors.forename: Thomas
authors.initials: T
authors.lastname: Januario
authors.forename: Christina P
authors.initials: CP
authors.lastname: Ahn
authors.forename: Thomas
authors.initials: T
authors.lastname: Holcomb
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Callahan
authors.forename: Tracy
authors.initials: T
authors.lastname: Tang
authors.forename: J Fernando
authors.initials: JF
authors.lastname: Bazan
authors.forename: Zhengyan
authors.initials: Z
authors.lastname: Kan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: Christine L
authors.initials: CL
authors.lastname: Hann
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Gould
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Low
authors.forename: Charles M
authors.initials: CM
authors.lastname: Rudin
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000813:Anilides / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002934:Cinnamates / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D053823:Hedgehog Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008527:Medulloblastoma / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D050505:Mutant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D020125:Mutation, Missense; D009362:Neoplasm Metastasis; D000072079:Patched Receptors; D011487:Protein Conformation; D011725:Pyridines / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids / Q000494:pharmacology
chemical_list: C542465:3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine; D000813:Anilides; D000970:Antineoplastic Agents; D002934:Cinnamates; D053823:Hedgehog Proteins; C538724:HhAntag691; D050505:Mutant Proteins; D000072079:Patched Receptors; D011725:Pyridines; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; C491023:SMO protein, human; C491022:Smo protein, mouse; D000072086:Smoothened Receptor; D014704:Veratrum Alkaloids