Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia
Hongqi Liu,
Xizhi Feng,
Kelli N. Ennis,
Catherine A. Behrmann,
Pranjal Sarma,
Tony T. Jiang,
Satoshi Kofuji,
Liang Niu,
Yiwen Stratton,
Hala Elnakat Thomas,
Sang-Oh Yoon,
Atsuo T. Sasaki,
David R. Plas
Affiliations
Hongqi Liu
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
Xizhi Feng
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA
Kelli N. Ennis
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
Catherine A. Behrmann
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA
Pranjal Sarma
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA
Tony T. Jiang
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA
Satoshi Kofuji
Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
Liang Niu
Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA
Yiwen Stratton
Eson Scientific, Inc., 1415 Kelvin Ct., Cincinnati, OH 45240-2334, USA
Hala Elnakat Thomas
Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA
Sang-Oh Yoon
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA
Atsuo T. Sasaki
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
David R. Plas
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; Corresponding author
Summary: 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. : Liu et al. find that the S6K1 inhibitor, AD80, is selectively cytotoxic for PTEN-deficient cancer cells, while LY-2779964 is ineffective as a single agent. AD80 avoids S6K1 priming and co-targets TAM tyrosine kinases. Combining LY-2779964 with the TAM kinase inhibitor BMS-777607 is selectively cytotoxic for PTEN-deficient cells. Keywords: S6K1, leukemia, LY-2779964, PF4708671, AD80, Pten, BMS-777607, AXL, TAM, glioblastoma
