Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

  • Cell Rep. 2017 Feb 28;18(9):2088-2095. doi: 10.1016/j.celrep.2017.02.022.
Hongqi Liu  1 ,  Xizhi Feng  2 ,  Kelli N Ennis  3 ,  Catherine A Behrmann  2 ,  Pranjal Sarma  2 ,  Tony T Jiang  2 ,  Satoshi Kofuji  4 ,  Liang Niu  5 ,  Yiwen Stratton  6 ,  Hala Elnakat Thomas  4 ,  Sang-Oh Yoon  2 ,  Atsuo T Sasaki  7 ,  David R Plas  8
Affiliations
  • 1. 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.
  • 2. Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
  • 3. 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.
  • 4. Division of Hematology-Oncology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH 45267, USA.
  • 5. Department of Environmental Health, University of Cincinnati, Cincinnati, OH 45267, USA.
  • 6. Eson Scientific, Inc., 1415 Kelvin Ct., Cincinnati, OH 45240-2334, USA.
  • 7. 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.
  • 8. 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: [email protected].
PMID: 28249155 DOI: 10.1016/j.celrep.2017.02.022
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.

Keywords
AD80; AXL; BMS-777607; LY-2779964; PF4708671; Pten; S6K1; TAM; glioblastoma; leukemia.
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