title: Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia.
abstract: Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of S6K1 inhibitors in PTEN-deficient T cell leukemia and glioblastoma. Results revealed that the S6K1 inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively in PTEN-deficient cells. In vivo, AD80 rescued 50% of mice transplanted with PTEN-deficient leukemia cells. Cells surviving LY-2779964 treatment exhibited inhibitor-induced S6K1 phosphorylation due to increased mTOR-S6K1 co-association, which primed the rapid recovery of S6K1 signaling. In contrast, AD80 avoided S6K1 phosphorylation and mTOR co-association, resulting in durable suppression of S6K1-induced signaling and protein synthesis. Kinome analysis revealed that AD80 coordinately inhibits S6K1 together with the TAM family tyrosine kinase AXL. TAM suppression by BMS-777607 or genetic knockdown potentiated cytotoxic responses to LY-2779964 in PTEN-deficient glioblastoma cells. These results reveal that combination targeting of S6K1 and TAMs is a potential strategy for treatment of PTEN-deficient malignancy.
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA; Institute of Medical Biology, Chinese Academy of Medical Science and Peking Union Medical College, Kunming, Yunnan 650118, China.
authors.forename: Hongqi
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
authors.forename: Xizhi
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA; Brain Tumor Center, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH 45219, USA.
authors.forename: Kelli N
authors.initials: KN
authors.lastname: Ennis
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Behrmann
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
authors.forename: Pranjal
authors.initials: P
authors.lastname: Sarma
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
authors.forename: Tony T
authors.initials: TT
authors.lastname: Jiang
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kofuji
authors.affiliation: Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Liang
authors.initials: L
authors.lastname: Niu
authors.affiliation: Eson Scientific, Inc., 1415 Kelvin Ct., Cincinnati, OH 45240-2334, USA.
authors.forename: Yiwen
authors.initials: Y
authors.lastname: Stratton
authors.affiliation: Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Hala Elnakat
authors.initials: HE
authors.lastname: Thomas
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
authors.forename: Sang-Oh
authors.initials: SO
authors.lastname: Yoon
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA; Brain Tumor Center, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH 45219, USA; Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: Atsuo T
authors.initials: AT
authors.lastname: Sasaki
authors.affiliation: Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA; Brain Tumor Center, University of Cincinnati Gardner Neuroscience Institute, Cincinnati, OH 45219, USA. Electronic address: plasd@uc.edu.
authors.forename: David R
authors.initials: DR
authors.lastname: Plas
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques / Q000379:methods; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006801:Humans; D015458:Leukemia, T-Cell / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D010766:Phosphorylation / Q000187:drug effects; D011728:Pyridones / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C574119:AD80 compound; D000631:Aminopyridines; D000970:Antineoplastic Agents; D006576:Heterocyclic Compounds, 4 or More Rings; C550356:N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide; D011728:Pyridones; D020794:Receptor Protein-Tyrosine Kinases; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase
keywords: AD80; AXL; BMS-777607; LY-2779964; PF4708671; Pten; S6K1; TAM; glioblastoma; leukemia