title: Combined Targeting of mTOR and Akt Using Rapamycin and MK-2206 in The Treatment of Tuberous Sclerosis Complex.
abstract: Tuberous sclerosis complex (TSC), caused by loss-of-function mutations in theTSC1orTSC2genes, 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 analyzingTsc1-orTsc2-null mouse embryonic fibroblasts (MEFs), we found that loss ofTSC1orTSC2led to a decreased sensitivity to MK-2206, a novel allosteric Akt inhibitor. Ectopic expression of a constitutively activated Akt (myristoylated Akt-1, myrAkt-1) sensitizedTsc2-null andTsc1-null MEFs to MK-2206. Furthermore, MK-2206 increased the cytotoxicity of rapamycin inTsc1-/-orTsc2-/-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.
authors.affiliation: Pulmonary Department, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China;; Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Shuang
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Stomatology, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China;; Department of Prosthodontics, Hospital of Stomatology, Wuhan University, Wuhan, Hubei, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Lin
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Zhaofei
authors.initials: Z
authors.lastname: Ni
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Fuquan
authors.initials: F
authors.lastname: Jin
authors.affiliation: Department of Biochemistry & Molecular Biology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, China.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Zha
authors.affiliation: Pulmonary Department, First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China.
authors.forename: Guanghe
authors.initials: G
authors.lastname: Fei
keywords: Akt; MK-2206; TSC; mTOR; rapamycin