據(jù)9月4日的《科學(xué)》雜志報(bào)道說(shuō),，新的分子學(xué)證據(jù)揭露了為什么一位接受一種有前途的治療轉(zhuǎn)移性髓母細(xì)胞瘤（這是一種生長(zhǎng)迅速的腦癌）的新藥的病人最終發(fā)展出了對(duì)這種藥物的抗藥性。
Hedgehog分子信號(hào)途徑在胚胎發(fā)育中扮演著一種根本性的作用,，它也對(duì)髓母細(xì)胞瘤的發(fā)展起著促進(jìn)作用,。 藥物GDC-0449的標(biāo)靶是Hedgehog通路中的Smoothened蛋白質(zhì)受體。在最近的一個(gè)臨床研究中,，一位接受該藥物治療的罹患晚期髓母細(xì)胞瘤的患者出現(xiàn)了腫瘤的急劇縮小,。 但是，該患者病情出現(xiàn)了復(fù)發(fā),。Robert Yauch及其同僚現(xiàn)在報(bào)告說(shuō),，在Smoothened中出現(xiàn)的一種獲得性突變使得該腫瘤對(duì)GDC-0449發(fā)生了抵抗力。 這種突變防止了該藥物與Smoothened受體的結(jié)合,。
理解這種抗藥機(jī)制可幫助研究人員設(shè)計(jì)更為有效的以Hedgehog 信號(hào)通路作為標(biāo)靶的抗癌藥物,。（生物谷Bioon.com）
生物谷推薦原始出處：
Science DOI: 10.1126/science.1179386 September 2, 2009
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 Sauvage 1*
1 Genentech, South San Francisco, CA 94080, USA.
2 The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21231, USA.
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.
