Rheb/mTOR activation and regulation in cancer: novel treatment strategies beyond rapamycin.
Rheb/mTOR activation and regulation in cancer: novel treatment strategies beyond rapamycin.
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DOI：
10.2174/138945011795906589
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发表时间：
2011-07
影响因子：
3.2
通讯作者：
Justin T. Babcock;L. Quilliam
中科院分区：
文献类型：
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作者：
Justin T. Babcock;L. Quilliam
mTOR 存在于两种不同的复合物中。 mTOR 复合物 1 (mTORC1) 被免疫抑制性大环内酯雷帕霉素有效抑制；然而，mTORC2 对此药物不敏感。这些 mTOR 复合物在许多细胞过程的调节中发挥着不可或缺的作用，包括蛋白质合成、自噬、脂质合成、线粒体代谢/生物发生和细胞周期。两种 mTOR 复合物对于维持细胞稳态和多种癌症的生长都很重要。雷帕霉素和雷帕霉素类似物仅能有效治疗少数癌症，并且正在开发其他方法以解决这些药物的缺点。这些方法中最直接的包括 mTOR 激酶的 ATP 竞争性抑制剂或 mTOR 和 PI3 激酶的双重抑制剂。然而，其他抑制 mTORC1 的方法也可能在临床上有用。这些包括使用天冬酰胺酶去除氨基酸以及使用法尼基转移酶抑制剂或他汀类药物抑制 Rheb GTP 酶。最令人兴奋的是，mTORC1 激活已被证明会导致细胞对 DNA 损伤和 ER 应激敏感。目前临床上用于治疗癌症的许多药物都会引起这些类型的应激，而现有的药物可能适合治疗具有高 mTORC1 活性的肿瘤。
mTOR exists in two distinct complexes. mTOR complex 1 (mTORC1) is potently inhibited by the immunosupressive macrolide rapamycin; whereas, mTORC2 is insensitive to this durg. These mTOR complexes play an integral role in the regulation of many cellular processes including protein synthesis, autophagy, lipid synthesis, mitochondrial metabolism/biogenesis, and cell cycle. Both mTOR complexes are important for maintaining cellular homeostasis and the growth of many types of cancer. Rapamycin and rapalogs have been effective in treating only a small number of these cancers, and other methods are being developed in order to address the short-comings of these drugs. The most direct of these approaches include ATP-competitive inhibitors of the mTOR kinase or dual inhibitors of both mTOR and PI3 kinase. However, other methods of inhibiting mTORC1 may prove clinically useful as well. These include amino acid depletion using asparaginase and inhibition of the Rheb GTPases with farnesyl transferase inhibitors or statins. Most excitingly, mTORC1 activation has been shown to cause and sensitize cells to DNA damage and ER stress. Many of the drugs currently used in the clinic for the treatment of cancer cause these types of stress, and existing drugs may be tailored to treat tumors with high mTORC1 activity.