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Targeting mTOR globally in cancer: thinking beyond rapamycin.

机译：在癌症中针对全球mTOR：雷帕霉素之外的思考。

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The mammalian target of rapamycin (mTOR) is centrally involved in growth, survival and metabolism. In cancer, mTOR is frequently hyperactivated and is a clinically validated target for drug development. Until recently, we have relied largely on the use of rapamycin to study mTOR function and its anticancer potential. Recent insights now indicate that rapamycin is a partial inhibitor of mTOR through allosteric inhibition of mTOR complex-1 (mTORC1) but not mTOR complex-2 (mTORC2). Both the mechanism of action and the cellular response to mTORC1 inhibition by rapamycin and related drugs may limit the effectiveness of these compounds as antitumor agents. We and others have recently reported the discovery of second-generation ATP-competitive mTOR kinase inhibitors (TKIs) that bind to the active sites of mTORC1 and mTORC2, thereby targeting mTOR signaling function globally (reviewed in refs. 1-4). The discovery of specific, active-site mTOR inhibitors has opened a new chapter in the 40-plus year old odyssey that began with the discovery of rapamycin from a soil sample collected on Easter Island (see Vezina C, et al. J Antibiot 1975). Here, we discuss recent studies that highlight the emergence of rapamycin-resistant mTOR function in protein synthesis, cell growth, survival and metabolism. It is shown that these rapamycin-resistant mTOR functions are profoundly inhibited by TKIs. A more complete suppression of mTOR global signaling network by the new inhibitors is expected to yield a deeper and broader antitumor response in the clinic.
机译：雷帕霉素（mTOR）的哺乳动物靶标主要参与生长，存活和代谢。在癌症中，mTOR经常被过度激活，并且是药物开发的临床验证靶标。直到最近，我们一直主要依靠雷帕霉素来研究mTOR功能及其抗癌潜力。现在的最新见解表明，雷帕霉素通过变构抑制mTOR complex-1（mTORC1）而不是mTOR complex-2（mTORC2）成为mTOR的部分抑制剂。雷帕霉素和相关药物对mTORC1抑制的作用机理和细胞应答都可能限制这些化合物作为抗肿瘤药的有效性。我们和其他人最近报道了发现第二代ATP竞争性mTOR激酶抑制剂（TKI），该抑制剂与mTORC1和mTORC2的活性位点结合，从而全面靶向mTOR信号传导功能（参见参考文献1-4）。特异性，活性位点mTOR抑制剂的发现开启了40多年历史的奥德赛的新篇章，从在复活节岛上收集的土壤样品中发现雷帕霉素开始（见Vezina C等人，J Antibiot 1975）。 。在这里，我们讨论了最近的研究，这些研究突出了雷帕霉素抗性mTOR功能在蛋白质合成，细胞生长，存活和代谢中的出现。结果表明，这些抗雷帕霉素的mTOR功能被TKIs强烈抑制。新型抑制剂对mTOR全球信号网络的更完全抑制有望在临床上产生更深，更广泛的抗肿瘤反应。

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