TY - JOUR
T1 - Smoothened mutation confers resistance to a hedgehog pathway inhibitor in medulloblastoma
AU - Yauch, Robert L.
AU - Dijkgraaf, Gerrit J.P.
AU - Alicke, Bruno
AU - Januário, Thomas
AU - Ahn, Christina P.
AU - Holcomb, Thomas
AU - Pujara, Kanan
AU - Stinson, Jeremy
AU - Callahan, Christopher A.
AU - Tang, Tracy
AU - Bazan, J. Fernando
AU - Kan, Zhengyan
AU - Seshagiri, Somasekar
AU - Hann, Christine L.
AU - Gould, Stephen E.
AU - Low, Jennifer A.
AU - Rudin, Charles M.
AU - De Sauvage, Frederic J.
PY - 2009/10/23
Y1 - 2009/10/23
N2 - 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.
AB - 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.
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U2 - 10.1126/science.1179386
DO - 10.1126/science.1179386
M3 - Article
C2 - 19726788
AN - SCOPUS:70350496540
SN - 0036-8075
VL - 326
SP - 572
EP - 574
JO - Science
JF - Science
IS - 5952
ER -