Science：突变阻断脑癌药物作用

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来源 EurekAlert! 2009-9-7 9:23:11
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据9月4日的《科学》杂志报道说，新的分子学证据揭露了为什么一位接受一种有前途的治疗转移性髓母细胞瘤（这是一种生长迅速的脑癌）的新药的病人最终发展出了对这种药物的抗药性。
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4 W9 r. R2 h4 m4 f4 G1 {  GHedgehog分子信号途径在胚胎发育中扮演着一种根本性的作用，它也对髓母细胞瘤的发展起着促进作用。 药物GDC-0449的标靶是Hedgehog通路中的Smoothened蛋白质受体。在最近的一个临床研究中，一位接受该药物治疗的罹患晚期髓母细胞瘤的患者出现了肿瘤的急剧缩小。 但是，该患者病情出现了复发。Robert Yauch及其同僚现在报告说，在Smoothened中出现的一种获得性突变使得该肿瘤对GDC-0449发生了抵抗力。 这种突变防止了该药物与Smoothened受体的结合。 # I6 E& c% b7 p1 Y% O+ N2 v: J
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理解这种抗药机制可帮助研究人员设计更为有效的以Hedgehog 信号通路作为标靶的抗癌药物。（生物谷Bioon.com）
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7 G) N  @, X: q7 h1 p5 WScience DOI: 10.1126/science.1179386 September 2, 20093 t& L; F! o" g# H8 J9 i- C* L, |& R
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Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma7 Q" y" E$ k! N8 ]! i+ T( [

* |: O# e3 K9 z8 I/ y3 qRobert 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 Sauvage 1*
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1 Genentech, South San Francisco, CA 94080, USA.
) g+ i5 Y6 N$ t7 a0 l5 P9 \2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
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" ?* E8 k6 m+ @  M) f6 }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 antitumor 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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