Liu Hongqi, Feng Xizhi, Ennis Kelli N, Behrmann Catherine A, Sarma Pranjal, Jiang Tony T, Kofuji Satoshi, Niu Liang, Stratton Yiwen, Thomas Hala Elnakat, Yoon Sang-Oh, Sasaki Atsuo T, Plas David R
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.
Department of Cancer Biology, Vontz Center for Molecular Studies, University of Cincinnati, Cincinnati, OH 45267-0521, USA.
Cell Rep. 2017 Feb 28;18(9):2088-2095. doi: 10.1016/j.celrep.2017.02.022.
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.
基因S6K1失活可诱导PTEN缺陷细胞凋亡。我们分析了S6K1抑制剂在PTEN缺陷的T细胞白血病和胶质母细胞瘤中的治疗潜力。结果显示，S6K1抑制剂LY-2779964作为单一药物相对无效，而靶向S6K1的AD80在PTEN缺陷细胞中选择性地诱导细胞毒性。在体内，AD80挽救了50%移植有PTEN缺陷白血病细胞的小鼠。经LY-2779964处理后存活的细胞由于mTOR-S6K1共结合增加而表现出抑制剂诱导的S6K1磷酸化，这引发了S6K1信号的快速恢复。相比之下，AD80避免了S6K1磷酸化和mTOR共结合，从而导致对S6K1诱导的信号传导和蛋白质合成的持久抑制。激酶组分析显示，AD80与TAM家族酪氨酸激酶AXL协同抑制S6K1。用BMS-777607抑制TAM或基因敲低增强了PTEN缺陷的胶质母细胞瘤细胞对LY-2779964的细胞毒性反应。这些结果表明，联合靶向S6K1和TAM是治疗PTEN缺陷恶性肿瘤的一种潜在策略。
