Targeting mTOR with rapamycin: one dose does not fit all.
Targeting mTOR with rapamycin: one dose does not fit all.
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DOI：
10.4161/cc.8.7.8044
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发表时间：
2009-04-01
期刊：
影响因子：
--
通讯作者：
Toschi A
中科院分区：
文献类型：
--
作者：
Foster DA;Toschi A
基于雷帕霉素的治疗策略的一个令人困惑的方面是在不同情况下抑制mTOR所需的剂量差异很大。最近的一项研究揭示了雷帕霉素如何抑制mTOR的机制，为雷帕霉素的不同敏感性提供了两种解释。首先，mTOR以两种功能不同的复合物（mTORC 1和mTORC 2）存在，虽然雷帕霉素抑制这两种复合物，但它的浓度非常不同。mTORC1在低nM范围的雷帕霉素浓度下受到抑制，而mTORC2通常需要低μM浓度。其次，雷帕霉素的功效取决于磷脂酸（PA）的水平，这是mTORC 1和mTORC 2复合物组装所需的。雷帕霉素以与PA竞争的方式与mTOR相互作用。因此，癌细胞中常见的PA水平升高会增加抑制mTORC 1和mTORC 2所需的雷帕霉素水平。最近研究的一个实际结果是，如果PA水平被抑制，mTORC 2对临床上可以达到的雷帕霉素浓度变得敏感。由于mTORC2可能对癌细胞的生存信号更关键，最近的研究结果提出了增强雷帕霉素治疗方法在癌细胞中疗效的新策略。
A puzzling aspect of rapamycin-based therapeutic strategies is the wide disparity in the doses needed to suppress mTOR under different circumstances. A recent study revealing mechanistically how rapamycin suppresses mTOR provides two explanations for the differential sensitivities to rapamycin. First, mTOR exists as two functionally distinct complexes (mTORC1 and mTORC2), and while rapamycin suppresses both, it does so at very different concentrations. Whereas mTORC1 is suppressed by concentrations of rapamycin in the low nM range, mTORC2 generally requires low μM concentrations. Second, the efficacy of rapamycin is dependent on the level of phosphatidic acid (PA), which is required for the assembly of both mTORC1 and mTORC2 complexes. Rapamycin interacts with mTOR in a manner that is competitive with PA. Therefore, elevated levels of PA, which is common in cancer cells, increases the level of rapamycin needed to suppress both mTORC1 and mTORC2. A practical outcome of the recent study is that if PA levels are suppressed, mTORC2 becomes sensitive to concentrations of rapamycin that can be achieved clinically. Since mTORC2 is likely more critical for survival signals in cancer cells, the recent findings suggest new strategies for enhancing the efficacy of rapamycin-based therapeutic approaches in cancer cells.
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DOI：
10.1158/1078-0432.ccr-08-0102
发表时间：
2008-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Garcia A;Zheng Y;Zhao C;Toschi A;Fan J;Shraibman N;Brown HA;Bar-Sagi D;Foster DA;Arbiser JL
通讯作者：
Arbiser JL
影响因子：
56.9
作者：
Fang, YM;Vilella-Bach, M;Chen, J
通讯作者：
Chen, J
影响因子：
50.3
作者：
Sawyers, CL
通讯作者：
Sawyers, CL
影响因子：
45.3
作者：
Fouladi, Maryam;Laningham, Fred;Furman, Wayne L.
通讯作者：
Furman, Wayne L.
影响因子：
4.3
作者：
Sun, Yuting;Chen, Jie
通讯作者：
Chen, Jie