A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity.
A diverse array of cancer-associated MTOR mutations are hyperactivating and can predict rapamycin sensitivity.
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各种各样的癌症相关MTOR突变是过度激活的，可以预测雷帕霉素的敏感性。
DOI：
10.1158/2159-8290.cd-13-0929
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发表时间：
2014-05
期刊：
影响因子：
28.2
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Grabiner BC;Nardi V;Birsoy K;Possemato R;Shen K;Sinha S;Jordan A;Beck AH;Sabatini DM
编码PI 3 K-Akt-mTOR信号传导轴组分的基因在癌症中经常突变，但在MTOR（mTOR激酶的基因）中很少有突变被表征。使用公开的肿瘤基因组测序数据，我们生成了癌症中mTOR通路突变的全面目录，确定了33个赋予通路过度激活的MTOR突变。这些突变聚集在mTOR C末端一半的六个不同区域，并发生在多种癌症类型中，其中一个簇在肾癌中特别突出。激活突变不影响mTOR复合物组装，但一个子集减少与mTOR抑制剂Deptor的结合。表达各种激活突变的细胞中的mTORC 1信号传导对药理学mTOR抑制仍然敏感，但对营养剥夺具有部分抗性。最后，具有过度活化的MTOR突变的癌细胞系在培养物中和作为体内异种移植物两者中显示出对雷帕霉素的敏感性提高，这表明此类突变赋予mTOR通路依赖性。
Genes encoding components of the PI3K-Akt-mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene for the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor Deptor. mTORC1 signaling in cells expressing various activating mutations remains sensitive to pharmacological mTOR inhibition, but is partially resistant to nutrient deprivation. Lastly, cancer cell lines with hyperactivating MTOR mutations display heightened sensitivity to rapamycin both in culture and as in vivo xenografts, suggesting that such mutations confer mTOR pathway dependency.