Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.
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.
Yauch
Robert L
RL
Genentech, South San Francisco, CA 94080, USA.
Dijkgraaf
Gerrit J P
GJ
Alicke
Bruno
B
Januario
Thomas
T
Ahn
Christina P
CP
Holcomb
Thomas
T
Pujara
Kanan
K
Stinson
Jeremy
J
Callahan
Christopher A
CA
Tang
Tracy
T
Bazan
J Fernando
JF
Kan
Zhengyan
Z
Seshagiri
Somasekar
S
Hann
Christine L
CL
Gould
Stephen E
SE
Low
Jennifer A
JA
Rudin
Charles M
CM
de Sauvage
Frederic J
FJ
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
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