Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy
Department of Biomedical and Neuromotor Sciences, University of Bologna, 40126 Bologna, Italy.
Clin Sci (Lond). 2018 Mar 9;132(5):543-568. doi: 10.1042/CS20171158. Print 2018 Mar 15.
Mechanistic target of rapamycin (mTOR) is the kinase subunit of two structurally and functionally distinct large multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTORC2. mTORC1 and mTORC2 play key physiological roles as they control anabolic and catabolic processes in response to external cues in a variety of tissues and organs. However, mTORC1 and mTORC2 activities are deregulated in widespread human diseases, including cancer. Cancer cells take advantage of mTOR oncogenic signaling to drive their proliferation, survival, metabolic transformation, and metastatic potential. Therefore, mTOR lends itself very well as a therapeutic target for innovative cancer treatment. mTOR was initially identified as the target of the antibiotic rapamycin that displayed remarkable antitumor activity Promising preclinical studies using rapamycin and its derivatives (rapalogs) demonstrated efficacy in many human cancer types, hence supporting the launch of numerous clinical trials aimed to evaluate the real effectiveness of mTOR-targeted therapies. However, rapamycin and rapalogs have shown very limited activity in most clinical contexts, also when combined with other drugs. Thus, novel classes of mTOR inhibitors with a stronger antineoplastic potency have been developed. Nevertheless, emerging clinical data suggest that also these novel mTOR-targeting drugs may have a weak antitumor activity. Here, we summarize the current status of available mTOR inhibitors and highlight the most relevant results from both preclinical and clinical studies that have provided valuable insights into both their efficacy and failure.
雷帕霉素靶蛋白（mTOR）是两种结构和功能上明显不同的大型多蛋白复合物的激酶亚基，分别称为 mTOR 复合物 1（mTORC1）和 mTORC2。mTORC1 和 mTORC2 发挥着关键的生理作用，因为它们可以控制各种组织和器官中对外界信号的合成代谢和分解代谢过程。然而，mTORC1 和 mTORC2 的活性在广泛的人类疾病中失调，包括癌症。癌细胞利用 mTOR 致癌信号来驱动其增殖、存活、代谢转化和转移潜能。因此，mTOR 非常适合作为创新癌症治疗的治疗靶点。mTOR 最初被鉴定为抗生素雷帕霉素的靶点，雷帕霉素具有显著的抗肿瘤活性。使用雷帕霉素及其衍生物（rapalogs）进行的有前途的临床前研究表明，它们对许多人类癌症类型有效，从而支持了许多旨在评估 mTOR 靶向治疗实际效果的临床试验的启动。然而，雷帕霉素和 rapalogs 在大多数临床情况下显示出非常有限的活性，即使与其他药物联合使用也是如此。因此，已经开发出了具有更强抗肿瘤活性的新型 mTOR 抑制剂。然而，新出现的临床数据表明，这些新型 mTOR 靶向药物也可能具有较弱的抗肿瘤活性。在这里，我们总结了现有 mTOR 抑制剂的现状，并强调了来自临床前和临床研究的最相关结果，这些结果为它们的疗效和失败提供了有价值的见解。
