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首页> 美国卫生研究院文献>Journal of Cancer >Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex
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Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex

机译：雷帕霉素和MK-2206联合靶向mTOR和Akt治疗结节性硬化症

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摘要

Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in the TSC1 or TSC2 genes, is an autosomal dominant disease characterized by benign tumor formation in multiple organs. Hyperactivation of mammalian target of rapamycin (mTOR) is the primary alteration underlying TSC tumor. Thus, rapamycin, as an mTOR specific inhibitor, has been assumed as a potential drug for the treatment of TSC. However, its application in TSC patients has been limited due to side effects. By analyzing Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs), we found that loss of TSC1 or TSC2 led to a decreased sensitivity to MK-2206, a novel allosteric Akt inhibitor. Ectopic expression of a constitutively activated Akt (myristoylated Akt-1, myrAkt-1) sensitized Tsc2-null and Tsc1-null MEFs to MK-2206. Furthermore, MK-2206 increased the cytotoxicity of rapamycin in Tsc1-/-or Tsc2-/- MEFs. Moreover, the benefit of the combinatorial treatment was also demonstrated in a TSC xenograft mouse model. We conclude that the combination of rapamycin and MK-2206 may be utilized as a new therapeutic regimen for TSC.
机译：由TSC1或TSC2基因的功能丧失突变引起的结节性硬化复合物（TSC）是常染色体显性疾病，其特征是在多个器官中形成良性肿瘤。雷帕霉素（mTOR）哺乳动物靶标的过度活化是TSC肿瘤的主要改变。因此，雷帕霉素作为mTOR特异性抑制剂被认为是治疗TSC的潜在药物。但是，由于副作用，它在TSC患者中的应用受到限制。通过分析Tsc1或Tsc2无效的小鼠胚胎成纤维细胞（MEFs），我们发现TSC1或TSC2的缺失导致对新型变构Akt抑制剂MK-2206的敏感性降低。组成型激活的Akt（肉豆蔻酰化的Akt-1，myrAkt-1）的异位表达使Tsc2-null和Tsc1-null MEF对MK-2206敏感。此外，MK-2206增加了雷帕霉素在Tsc1 -/-或Tsc2 -/- MEF中的细胞毒性。此外，在TSC异种移植小鼠模型中也证明了组合治疗的益处。我们得出的结论是，雷帕霉素和MK-2206的组合可以用作TSC的新治疗方案。

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