Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma

被引：700

作者：

Yauch, Robert L. ^{[1
]}

Dijkgraaf, Gerrit J. P. ^{[1
]}

Alicke, Bruno ^{[1
]}

Januario, Thomas ^{[1
]}

Ahn, Christina P. ^{[1
]}

Holcomb, Thomas ^{[1
]}

Pujara, Kanan ^{[1
]}

Stinson, Jeremy ^{[1
]}

Callahan, Christopher A. ^{[1
]}

Tang, Tracy ^{[1
]}

Bazan, J. Fernando ^{[1
]}

Kan, Zhengyan ^{[1
]}

Seshagiri, Somasekar ^{[1
]}

Hann, Christine L. ^{[2
]}

Gould, Stephen E. ^{[1
]}

Low, Jennifer A. ^{[1
]}

Rudin, Charles M. ^{[2
]}

de Sauvage, Frederic J. ^{[1
]}

机构：

[1] Genentech Inc, San Francisco, CA 94080 USA

[2] Johns Hopkins Univ, Sidney Kimmel Comprehens Canc Ctr, Baltimore, MD 21231 USA

来源：

SCIENCE | 2009年 / 326卷 / 5952期

关键词：

PROTEIN-COUPLED RECEPTORS; CYCLOPAMINE; CANCER;

D O I：

10.1126/science.1179386

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：572 / 574

页数：3

共 16 条

[1] Inhibition of Hedgehog signaling by direct binding of cyclopamine to Smoothened [J].