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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Amino Acid Substitution
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Anilides / metabolism
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Anilides / pharmacology
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Anilides / therapeutic use*
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Animals
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Antineoplastic Agents / metabolism
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use*
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Brain Neoplasms / drug therapy*
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Brain Neoplasms / genetics*
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Brain Neoplasms / pathology
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Cell Line, Tumor
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Cinnamates / pharmacology
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Drug Resistance, Neoplasm
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Hedgehog Proteins / antagonists & inhibitors
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Hedgehog Proteins / genetics
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Hedgehog Proteins / metabolism*
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Humans
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Medulloblastoma / drug therapy*
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Medulloblastoma / genetics*
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Medulloblastoma / pathology
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Mice
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Molecular Sequence Data
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Mutant Proteins / antagonists & inhibitors
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Mutant Proteins / chemistry
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Mutant Proteins / metabolism
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Mutation, Missense
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Neoplasm Metastasis
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Patched Receptors
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Protein Conformation
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Pyridines / metabolism
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Pyridines / pharmacology
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Pyridines / therapeutic use*
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Receptors, Cell Surface / genetics
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Receptors, Cell Surface / metabolism
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Receptors, G-Protein-Coupled / antagonists & inhibitors
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Receptors, G-Protein-Coupled / chemistry
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Receptors, G-Protein-Coupled / genetics*
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Receptors, G-Protein-Coupled / metabolism
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Signal Transduction
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Smoothened Receptor
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Veratrum Alkaloids / pharmacology
Substances
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3-keto-N-aminoethylaminoethylcaproyldihydrocinnamoyl cyclopamine
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Anilides
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Antineoplastic Agents
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Cinnamates
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Hedgehog Proteins
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HhAntag691
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Mutant Proteins
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Patched Receptors
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Pyridines
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Receptors, Cell Surface
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Receptors, G-Protein-Coupled
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SMO protein, human
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Smo protein, mouse
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Smoothened Receptor
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Veratrum Alkaloids