eIF4E/4E-BP Ratio Predicts the Efficacy of mTOR Targeted Therapies
eIF4E/4E-BP Ratio Predicts the Efficacy of mTOR Targeted Therapies
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DOI：
10.1158/0008-5472.can-12-2395
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发表时间：
2012-12-15
期刊：
影响因子：
11.2
通讯作者：
Sonenberg, Nahum
中科院分区：
文献类型：
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作者：
Alain, Tommy;Morita, Masahiro;Sonenberg, Nahum
活性位点mTOR抑制剂（asTORi）在靶向癌症中失调的mTOR信号传导方面具有很大的前景。由于mTORC1信号的多面性，确定肿瘤对asTORi敏感性的可靠生物标志物对于其临床应用至关重要。在这里，我们发现癌细胞通过下调真核翻译起始因子（eIF4E）结合蛋白（4E-BPs-EIF4EBP1, EIF4EBP2）获得对asTORi的抗性。4e - bp的缺失或eIF4E的过度表达使得肿瘤生长和肿瘤促进mrna的翻译难以抑制mTOR。相反，适度减少eIF4E可增强asTORi的抗肿瘤作用。因此，在体外和体内，asTORi的抗增殖作用受到eIF4E/4E-BP化学计量的显著影响，因此，eIF4E/4E-BP比值的增加显著限制了癌细胞对asTORi的敏感性。我们建议，eIF4E/4E-BP比值，而不是它们的个体蛋白水平或仅仅是它们的磷酸化状态，应该被视为预测mTOR抑制剂临床治疗反应的重要预测指标。癌症Res;72 (24);6468 - 76。(c) 2012年AACR。
Active-site mTOR inhibitors (asTORi) hold great promise for targeting dysregulated mTOR signaling in cancer. Because of the multifaceted nature of mTORC1 signaling, identification of reliable biomarkers for the sensitivity of tumors to asTORi is imperative for their clinical implementation. Here, we show that cancer cells acquire resistance to asTORi by downregulating eukaryotic translation initiation factor (eIF4E)-binding proteins (4E-BPs-EIF4EBP1, EIF4EBP2). Loss of 4E-BPs or overexpression of eIF4E renders neoplastic growth and translation of tumor-promoting mRNAs refractory to mTOR inhibition. Conversely, moderate depletion of eIF4E augments the anti-neoplastic effects of asTORi. The anti-proliferative effect of asTORi in vitro and in vivo is therefore significantly influenced by perturbations in eIF4E/4E-BP stoichiometry, whereby an increase in the eIF4E/4E-BP ratio dramatically limits the sensitivity of cancer cells to asTORi. We propose that the eIF4E/4E-BP ratio, rather than their individual protein levels or solely their phosphorylation status, should be considered as a paramount predictive marker for forecasting the clinical therapeutic response to mTOR inhibitors. Cancer Res; 72(24); 6468-76. (c) 2012 AACR.