Abstract 3750: The novel Akt inhibitor MK-2206, is cytotoxic in T-cell acute lymphoblastic leukemia: Therapeutic implications

Abstract

Abstract T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive neoplastic disorder arising within the thymus from the clonal proliferation of T-cell precursors. T-ALL accounts for 15% of ALL cases in children and 25% in adults. Although the prognosis of T-ALL has improved, due to the use of intensive polychemotherapy schemes, the outcome of relapsed and chemoresistant T-ALL is still poor, especially in adults, with a 35-40% survival at 5 years. Therefore, efforts are being made to develop targeted therapies against deregulated signaling cascades that sustain T-ALL cell proliferation, survival, and drug-resistance. A signaling pathway that is frequently upregulated in T-ALL, is the PI3K/Akt/mTOR network. To explore whether or not Akt could represent a potential target for therapeutic intervention in T-ALL, we evaluated the effects of the novel allosteric Akt inhibitor, MK-2206, on a panel of human T-ALL cell lines (MOLT-4, CEM, drug-resistant CEM) and primary cells from T-ALL patients, characterized by pathway upregulation. MK-2206 decreased T-ALL cell line viability as documented by MTT assays. IC50 for MK-2206 ranged from 1.0 to 4.8 μM at 48 hours. The drug was effective against drug-resistant CEM cells, overexpressing 170-kDa P-glycoprotein. MK-2206 blocked leukemic cells in the G1 phase of the cell cycle and induced caspase-dependent apoptotic cell death, as documented by Annexin V/propidium iodide staining and western blot analysis. In CEM cells, MK-2206 induced autophagy, as demonstrated by an increase in the 14-kDa form of LC3A/B. Western blotting documented a concentration-dependent dephosphorylation of Akt and its downstream targets, GSK-3β and FOXO3A, in response to MK-2206. mTORC1 downstream targets were also efficiently dephosphorylated by MK-2206, including p70S6K and 4E-BP1. MK-2206 decreased mTORC2 activity, as indicated by the downregulation of Ser 2481 p-mTOR levels, a readout for mTORC2 activity In MOLT-4 and CEM cells, MK-2206 strongly synergized (combination index: 0.1-0.33) with doxorubicin. Moreover, MK-2206 dephosphorylated Akt and induced apoptosis in a T-ALL patient cell subset (CD34+/CD4−/CD7−) which is enriched in leukemia initiating cells. Our findings indicate that Akt inhibition, either alone or in combination with chemotherapeutic drugs, represents a potential therapeutic target in T-ALL cells that require upregulation of the PI3K/Akt/mTOR signaling pathway for their proliferation and survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3750. doi:1538-7445.AM2012-3750