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mTOR是处于调节细胞代谢、生长、增殖等整个过程中心环节的重要激酶。干扰或抑制mTOR会引起细胞尤其是癌细胞的生长停滞继而死亡,因而也被公认为是癌症治疗当中的一个潜在靶标。一系列的mTOR抑制剂Rapamycin及类似物已经形成并在临床抗肿瘤中有所应用,但其展示的效应非常有限。随着研究的深入,发现mTOR信号通路存在反馈激活机制:即抑制mTOR能反馈性激活多个与细胞生长增殖相关的信号通路。并且认为是这些反馈激活机制削弱了mTOR抑制剂的效能,也是其临床效应未达预期的原因。本文就目前国内外研究较深入的mTOR-AKT,mTOR-ERK,mTOR-eIF4E反馈信号通路做详细概述,并阐述目前采取的防止这一反馈机制形成的Rapamycin类似物与特定通路抑制剂的联合用药策略,使mTOR抑制剂在临床抗肿瘤中能充分发挥其效能。
mTOR is an important kinase in the heart of the whole process of regulating cell metabolism, growth and proliferation. Interfering or inhibiting mTOR causes the arrest and subsequent death of cells, especially cancer cells, and is therefore also recognized as a potential target for cancer therapy. A series of Rapamycin and its analogs, mTOR inhibitors, have been developed and used clinically for antitumor activity, but show limited efficacy. With the deepening of research, we found that there is a feedback activation mechanism in mTOR signaling pathway: that is, inhibiting mTOR can feedback-activate multiple signaling pathways related to cell proliferation. And it is believed that these feedback activation mechanisms impair the potency of mTOR inhibitors and are also the cause of their undefined clinical effects. In this paper, we present a detailed overview of the mTOR-AKT, mTOR-ERK, and mTOR-eIF4E feedback signaling pathways that are currently being studied at home and abroad. We also present the currently used combination of Rapamycin analogs and specific pathway inhibitors that prevent the formation of this feedback mechanism Strategy, mTOR inhibitors in clinical anti-tumor can give full play to its effectiveness.