Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

Publication date: 28 February 2017
Source:Cell Reports, Volume 18, Issue 9
Author(s): 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
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.

Graphical abstract

Teaser

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.


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