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Cell Rep. 2017 Feb 28;18(9):2088-2095. doi: 10.1016/j.celrep.2017.02.022.

Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia.

Author information

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.

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

PMID:
28249155
PMCID:
PMC5374978
DOI:
10.1016/j.celrep.2017.02.022
[Indexed for MEDLINE]
Free PMC Article

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