Abstract LB-027: Inhibition of mammalian target of rapamycin by Torin2, an ATP-competitive inhibitor, induces growth inhibition in adult T cell leukemia

Abstract

Abstract Adult T cell leukemia (ATL) is one of the aggressive malignant lymphomas induced by the infection of human T-cell Lymphotropic virus-1. Advanced stages of ATL patients still have a poor prognosis and novel therapeutic approaches are needed. Since mammalian target of rapamycin (mTOR) is a key molecule in cell growth and survival in a number of hematological malignancies, we here focused on mTOR signaling pathway consisting from mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). It has been already reported that inhibition of mTOR with rapamycin, a classical mTOR inhibitor, or its derivatives induces growth inhibition in ATL cells, and we found that Torin2, a second generation ATP-competitive mTOR inhibitor, has more beneficial effects than rapamycin does. Although Torin2 showed weaker growth inhibitory effect against ATL cell lines than rapamycin did at low concentrations (< 10 nM), its effect exceeded at higher concentrations (> 10nM) in CCK-8 assay and Trypan blue staining assay. To understand differences of mechanism of action between Torin2 and rapamycin, we first studied apoptosis and cell cycle arrest of the ATL cell line stained with annexin-FITC; Although both Torin2 and rapamycin caused G1 cell cycle arrest, a small number of ATL cells died in apoptotic manner at higher concentration of Torin2 but not of rapamycin. It is important to note that inhibition of mTOR pathway with rapamycin induced feedback activation of Akt (phosphorylation of Akt at Ser471), down stream of mTORC2, at high concentrations (> 50 nM) but Torin2 inhibited phosphorylation of Akt dose-dependently. Based on these results, we think Torin2 inhibits mTORC1 and mTORC2 followed by G1 cell cycle arrest, however rapamycin inhibits only mTORC1 and it induces feedback activation of Akt at high concentration resulting in resistance to apoptotic cell death. Thus, inhibition of mTOR pathway with Torin2 is new potent therapeutic approach in the treatment of ATL. Citation Format: Tatsuro Watanabe, Naoko Aragane, Eisaburo Sueoka. Inhibition of mammalian target of rapamycin by Torin2, an ATP-competitive inhibitor, induces growth inhibition in adult T cell leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-027. doi:10.1158/1538-7445.AM2015-LB-027