2009-9-2 Science：更有效的Hedgehog抗癌靶位

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来源 生物通 2009-9-10 12:58:20
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  I0 r  W0 ]: _% h. N& I3 w& TScience：更有效的Hedgehog抗癌靶位+ W' I" l$ Z- _* t5 f+ T

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  f$ r3 d: f$ N5 v: M# i1 \Johns Hopkins大学Sidney Kimmel癌症综合研究中心、Genentech公司的科学家在最新一期的Science杂志上发表Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma文章，解析以Hedgehog为靶位的更为有效的抗药药物。5 k( X9 ~7 c& T& W- I. P0 K6 R

+ w$ G6 o+ J( F$ f3 z文章通讯作者是Genetech公司的副总裁，分子生物学方面的首席科学家。8 f8 S7 f7 K5 ]( H

. {' N) D3 q  g. W$ x; N6 bHedgehog基因是一种分节极性基因，因突变的果蝇胚胎呈多毛团状，酷似受惊刺猬而得名。已知该基因编码一种高度保存的分泌型糖蛋白，对于调节果蝇胚胎发育中细胞定向分化有重要作用。
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1 I5 ]& B0 D0 m( H7 N) V2 W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。  Hedgehog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。+ ]& ?0 a; O) x

; ~0 q5 K8 x. I4 C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。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。) Y3 _1 `4 @3 m( V7 n  m

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2 q) `! s7 a: s# `+ LScience DOI: 10.1126/science.1179386 September 2, 2009( U- y  `0 R8 \8 S. J& ~$ X, N
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Smoothened Mutation Confers Resistance to a Hedgehog Pathway Inhibitor in Medulloblastoma2 e9 j& O, W. O

( m( t) ]# V$ J9 b0 W- _+ mRobert 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*# W$ Y" Y2 d: y9 M. @, w  u

- h4 l! S$ J$ ]8 O) I1 Genentech, South San Francisco, CA 94080, USA.5 Q( d2 r( B* C+ @
2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.$ a2 @6 a3 s9 m) _* S$ [! p* i* }

4 t0 t6 W9 x5 n: f! A. ZThe 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.