title: Dual mTORC1/mTORC2 inhibition diminishes Akt activation and induces Puma-dependent apoptosis in lymphoid malignancies.
abstract: The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, up-regulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo.
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: Mamta
authors.initials: M
authors.lastname: Gupta
authors.forename: Andrea E Wahner
authors.initials: AE
authors.lastname: Hendrickson
authors.forename: Seong Seok
authors.initials: SS
authors.lastname: Yun
authors.forename: Jing Jing
authors.initials: JJ
authors.lastname: Han
authors.forename: Paula A
authors.initials: PA
authors.lastname: Schneider
authors.forename: Brian D
authors.initials: BD
authors.lastname: Koh
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Stenson
authors.forename: Linda E
authors.initials: LE
authors.lastname: Wellik
authors.forename: Jennifer C
authors.initials: JC
authors.lastname: Shing
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Peterson
authors.forename: Karen S
authors.initials: KS
authors.lastname: Flatten
authors.forename: Allan D
authors.initials: AD
authors.lastname: Hess
authors.forename: B Douglas
authors.initials: BD
authors.lastname: Smith
authors.forename: Judith E
authors.initials: JE
authors.lastname: Karp
authors.forename: Sharon
authors.initials: S
authors.lastname: Barr
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Witzig
authors.forename: Scott H
authors.initials: SH
authors.lastname: Kaufmann
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D047468:Immunoprecipitation; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008223:Lymphoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D046912:Multiprotein Complexes; D010766:Phosphorylation / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D014227:Triazines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D051017:Apoptosis Regulatory Proteins; C438378:BBC3 protein, human; C493245:CRTC2 protein, human; D007093:Imidazoles; D007166:Immunosuppressive Agents; D046912:Multiprotein Complexes; C568605:OSI 027; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D014227:Triazines; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
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