2. Academic Validation
  3. Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

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

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: plasd@uc.edu.
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.

Figures
Products