title: Inhibition of the mTORC2 and chaperone pathways to treat leukemia.
abstract: Constitutive activation of the kinases Akt or protein kinase C (PKC) in blood cancers promotes tumor-cell proliferation and survival and is associated with poor patient survival. The mammalian target of rapamycin (mTOR) complex 2 (mTORC2) regulates the stability of Akt and conventional PKC (cPKC; PKCα and PKCβ) proteins by phosphorylating the highly conserved turn motif of these proteins. In cells that lack mTORC2 function, the turn motif phosphorylation of Akt and cPKC is abolished and therefore Akt and cPKC protein stability is impaired. However, the chaperone protein HSP90 can stabilize Akt and cPKC, partially rescuing the expression of these proteins. In the present study, we investigated the antitumor effects of inhibiting mTORC2 plus HSP90 in mouse and human leukemia cell models and show that the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG) preferentially inhibits Akt and cPKC expression and promotes cell death in mTORC2 deficient pre-B leukemia cells. Furthermore, we show that 17-AAG selectively inhibits mTORC2 deficient leukemia cell growth in vivo. Finally, we show that the mTOR inhibitors rapamycin and pp242 work together with 17-AAG to inhibit leukemia cell growth to a greater extent than either drug alone. These studies provide a mechanistic and clinical rationale to combine mTOR inhibitors with chaperone protein inhibitors to treat human blood cancers.
authors.affiliation: Department of Immunobiology and Vascular Biology and Therapeutic Program, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Adam S
authors.initials: AS
authors.lastname: Lazorchak
authors.forename: Dou
authors.initials: D
authors.lastname: Liu
authors.forename: Fangping
authors.initials: F
authors.lastname: Chen
authors.forename: Bing
authors.initials: B
authors.lastname: Su
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016227:Benzoquinones / Q000008:administration & dosage; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D018841:HSP90 Heat-Shock Proteins / Q000037:antagonists & inhibitors; D006801:Humans; D007211:Indoles / Q000008:administration & dosage; D019169:Jurkat Cells; D047029:Lactams, Macrocyclic / Q000008:administration & dosage; D007938:Leukemia / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D018832:Molecular Chaperones / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011687:Purines / Q000008:administration & dosage; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020123:Sirolimus / Q000008:administration & dosage; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D015534:Trans-Activators / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D016227:Benzoquinones; C504923:Crtc2 protein, mouse; D018841:HSP90 Heat-Shock Proteins; D007211:Indoles; D047029:Lactams, Macrocyclic; D018832:Molecular Chaperones; D011687:Purines; D015534:Trans-Activators; D014157:Transcription Factors; C112765:tanespimycin; D058570:TOR Serine-Threonine Kinases; C572919:PP242; D020123:Sirolimus