Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma by Yauch Robert L, Dijkgraaf Gerrit J P, Alicke Bruno, Januario Thomas, Ahn Christina P, Holcomb Thomas, Pujara Kanan, Stinson Jeremy, Callahan Christopher A, Tang Tracy, Bazan J Fernando, Kan Zhengyan, Seshagiri Somasekar, Hann Christine L, Gould Stephen E, Low Jennifer A, Rudin Charles M, de Sauvage Frederic J in Science (New York, N.Y.) (2009).

[PMID: 19726788] PubMed


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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