Pharmacologic Targeting of S6K1 in PTEN-Deficient Neoplasia

• DOI: 10.1016/j.celrep.2017.02.022
• Publication Date: 2017-03-01T04:14:58Z
• Authors: Hongqi Liu; Xizhi Feng; Kelli N. Ennis; Catherine A. Behr...; Pranjal Sarma; Tony T. Jiang; Satoshi Kofuji; Liang Niu; Yiwen Stratton; Hala Elnakat Thomas; Sang-Oh Yoon; Atsuo T. Sasaki; David R. Plas
• Keywords: 0301 basic medicine; 0303 health sciences; Leukemia, T-Cell; QH301-705.5; Pyridones; TOR Serine-Threonine Kinases; PTEN Phosphohydrolase; Aminopyridines; Receptor Protein-Tyrosine Kinases; Ribosomal Protein S6 Kinases, 70-kDa; Antineoplastic Agents; Apoptosis; Heterocyclic Compounds, 4 or More Rings; 3. Good health; Mice; 03 medical and health sciences; Cell Line, Tumor; Gene Knockdown Techniques; Neoplasms; Animals; Humans; Biology (General); Phosphorylation; Glioblastoma; Signal Transduction

Genetic S6K1 inactivation can induce apoptosis in PTEN-deficient cells. We analyzed the therapeutic potential of inhibitors T cell leukemia and glioblastoma. Results revealed that inhibitor LY-2779964 was relatively ineffective as a single agent, while S6K1-targeting AD80 induced cytotoxicity selectively In vivo, rescued 50% mice transplanted with Cells surviving treatment exhibited inhibitor-induced phosphorylation due to increased mTOR-S6K1 co-association, which primed rapid recovery signaling. contrast, avoided mTOR resulting durable suppression S6K1-induced signaling protein synthesis. Kinome analysis coordinately inhibits together TAM family tyrosine kinase AXL. by BMS-777607 or genetic knockdown potentiated cytotoxic responses glioblastoma These results reveal combination targeting TAMs is strategy for malignancy.