Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex.
Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex.
复制标题
使用雷帕霉素和 MK-2206 联合靶向 mTOR 和 Akt 治疗结节性硬化症
DOI：
10.7150/jca.17205
复制
发表时间：
2017
影响因子：
3.9
通讯作者：
Fei G
中科院分区：
文献类型：
--
作者：
Ji S;Lin W;Wang L;Ni Z;Jin F;Zha X;Fei G
多发性硬化症（TSC）是由TSC 1或TSC 2基因功能缺失突变引起的常染色体显性遗传疾病，其特征是多器官良性肿瘤形成。哺乳动物雷帕霉素靶蛋白（mTOR）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。然而，由于副作用，其在TSC患者中的应用受到限制。通过分析Tsc 1或Tsc 2缺失的小鼠胚胎成纤维细胞（MEFs），我们发现TSC 1或TSC 2的缺失导致对MK-2206（一种新型变构Akt抑制剂）的敏感性降低。异位表达组成性激活的Akt（豆蔻酰化Akt-1，myrAkt-1）使Tsc 2-null和Tsc 1-null MEFs对MK-2206敏感。此外，MK-2206增加了Tsc 1-/-或Tsc 2-/- MEFs中雷帕霉素的细胞毒性。此外，还在TSC异种移植小鼠模型中证明了组合治疗的益处。我们的结论是，雷帕霉素和MK-2206的组合可用作TSC的新的治疗方案。
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.