Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.
Smoothened mutation confers resistance to a Hedgehog pathway inhibitor in medulloblastoma.
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DOI：
10.1126/science.1179386
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发表时间：
2009-10-23
期刊：
影响因子：
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通讯作者：
de Sauvage FJ
中科院分区：
文献类型：
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作者：
Yauch RL;Dijkgraaf GJ;Alicke B;Januario T;Ahn CP;Holcomb T;Pujara K;Stinson J;Callahan CA;Tang T;Bazan JF;Kan Z;Seshagiri S;Hann CL;Gould SE;Low JA;Rudin CM;de Sauvage FJ
Hedgehog （Hh）信号通路在某些人类癌症中被不当激活，包括髓母细胞瘤（一种侵袭性脑肿瘤）。GDC-0449是一种通过靶向蛇纹石受体Smoothened （SMO）抑制Hh信号的药物，在该途径突变驱动的癌症的早期临床研究中产生了有希望的抗肿瘤反应。为了评估一名最初对GDC-0449有反应后复发的髓母细胞瘤患者的耐药机制，我们确定了疾病进展后肿瘤中Hh信号基因的突变状态。我们在SMO的一个保守的天冬氨酸残基上发现了一个氨基酸取代，它对Hh信号传导没有影响，但破坏了GDC-0449结合SMO并抑制这一途径的能力。在抗gdc -0449的成神经管细胞瘤小鼠模型中也出现了改变相同氨基酸的突变。这些发现表明，具有G蛋白偶联受体特征的蛇形受体的获得性突变可以作为人类癌症耐药的机制之一。
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.