Targeting mTOR globally in cancer Thinking beyond rapamycin
Targeting mTOR globally in cancer Thinking beyond rapamycin
复制标题
DOI：
10.4161/cc.8.23.10070
复制
发表时间：
2009-12-01
期刊：
影响因子：
4.3
通讯作者：
Yu, Ker
中科院分区：
文献类型：
--
作者：
Shor, Boris;Gibbons, James J.;Yu, Ker
哺乳动物雷帕霉素靶蛋白（mTOR）主要参与生长、存活和代谢。在癌症中，mTOR经常被过度激活，并且是临床验证的药物开发靶点。直到最近，我们主要依赖于使用雷帕霉素来研究mTOR功能及其抗癌潜力。最近的见解现在表明，雷帕霉素是mTOR的部分抑制剂，通过变构抑制mTOR复合物-1（mTORC 1）而不是mTOR复合物-2（mTORC 2）。雷帕霉素和相关药物对mTORC 1抑制的作用机制和细胞反应可能限制这些化合物作为抗肿瘤剂的有效性。我们和其他人最近报告了第二代ATP竞争性mTOR激酶抑制剂（TKI）的发现，它们与mTORC 1和mTORC 2的活性位点结合，从而在全球范围内靶向mTOR信号传导功能（参考文献中综述）。第1-4段）。特异性、活性位点mTOR抑制剂的发现开启了40多年漫长历程的新篇章，这一历程始于从复活节岛采集的土壤样品中发现雷帕霉素（参见Vezina C等，J Antibiot 1975）。在这里，我们讨论了最近的研究，强调了雷帕霉素耐药mTOR功能的出现在蛋白质合成，细胞生长，存活和代谢。研究表明，这些雷帕霉素耐药性mTOR功能受到TKI的严重抑制。新抑制剂对mTOR全局信号网络的更完全抑制预期将在临床中产生更深和更广泛的抗肿瘤反应。
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.