Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia.

Effects of Neddylation and mTOR Inhibition in Acute Myelogenous Leukemia. Transl Oncol. 2019 Jan 27;12(4):602-613 Authors: Guo N, Azadniv M, Coppage M, Nemer M, Mendler J, Becker M, Liesveld J Abstract Acute myelogenous leukemia (AML) is a heterogeneous disease and often relapses after standard chemotherapy. Recently, the neddylation (NEDD8) and the mammalian target of rapamycin (mTOR) signaling pathways have emerged as promising pharmaceutical targets for AML therapy. However, the interaction of these two pathways remains unclear. Here we evaluated the effects of pevonedistat, an inhibitor of the NEDD8 activating enzyme (NAE), and sapanisertib (TAK-228), an inhibitor of mTORC1 and mTORC2 as single agents or in combination on AML cell lines. We found that inhibition of neddylation with pevonedistat partially inhibited mTOR signaling transduction and vice versa, inhibition of mTOR signaling with sapanisertib partially inhibited neddylation in AML cell lines. Pevonedistat alone was able to induce cytotoxicity in most AML cell lines as well as in primary AML, whereas sapanisertib alone decreased cell metabolic activity, reduced cell size and arrested cells in G0 phase with only minimal induction of cell death. In addition, pevonedistat was able to induce cell differentiation, arrest cells in G2/M cell cycle phases, and induce DNA re-replication and damage. However, co-treatment with sapanisertib suppressed pevonedistat induced apoptosis...
Source: Translational Oncology - Category: Cancer & Oncology Authors: Tags: Transl Oncol Source Type: research