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Science 326 (5952): 572-574

Copyright © 2009 by the American Association for the Advancement of Science

Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma

Robert L. Yauch,1 Gerrit J. P. Dijkgraaf,1 Bruno Alicke,1 Thomas Januario,1 Christina P. Ahn,1 Thomas Holcomb,1 Kanan Pujara,1 Jeremy Stinson,1 Christopher A. Callahan,1 Tracy Tang,1 J. Fernando Bazan,1 Zhengyan Kan,1 Somasekar Seshagiri,1 Christine L. Hann,2 Stephen E. Gould,1 Jennifer A. Low,1 Charles M. Rudin,2 Frederic J. de Sauvage1,*

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.

1 Genentech, South San Francisco, CA 94080, USA.
2 Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.

* To whom correspondence should be addressed. E-mail: sauvage{at}

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