Abstract 3659: The AKT inhibitor MK-2206 promotes apoptosis in acute myeloid leukemia cells
Authors: Ruvolo Peter P. , Zeng Zhihong , Ruvolo Vivian R. , Borthakur Gautam , Kornblau Steven M. , Andreeff Michael , Konopleva Marina 
Published: August 2012

The need for improved therapies for acute myeloid leukemia (AML) is urgent as the disease is still highly fatal. Protein Kinase B (AKT) activation has been shown to predict poor clinical outcome for patients with AML. In 253 newly diagnosed AML cases, we have found that AKT phosphorylation on Thr308 analyzed by reverse-phase protein arrays was significantly higher in patients with unfavorable cytogenetics (p=0.037). The adverse prognostic factor of high levels of pAKT was observed among patients with intermediate-risk cytogenetics (p=0.013), as it was associated with an inferior survival (median survival 44.2 weeks) compared to patients with low or intermediate pAKT (78.7 weeks). Recently, Merck Sharp & Dohme Corp. has developed a compound, MK-2206, that is a highly specific allosteric inhibitor for all three AKT isoforms. In the current study, we have determined that MK-2206 as a single agent used at clinically achievable concentrations suppresses cell growth of a variety of AML derived cell lines including OCI-AML3, U937, and MOLM13. MK-2206 can also induce apoptosis in blast cells derived from AML patients. Consistent with its role as an AKT inhibitor, the drug suppresses phosphorylation of AKT at serine 473 and inhibits phosphorylation of AKT downstream targets including S6 ribosomal protein, 4-EBP1, and PRAS40 in the AML cells. We recently identified that low expression of the PP2A isoform that acts as the AKT phosphatase (i.e. the one containing the B55α subunit) in AML negatively correlates with AKT T308 phosphorylation and activation in a cohort of 511 AML patients (Ruvolo et al Leukemia, 2011). Patients with low B55α expression exhibited shorter complete remission duration. We suppressed B55α expression by shRNA in OCI-AML3 cells to determine if loss of the AKT phosphatase promotes AKT activation and chemoresistance. Cells with reduced B55α exhibited higher levels of AKT phosphorylation and were more resistant to killing by the conventional chemotherapy agent AraC. OCI-AML3 B55α shRNA transductant cells were also more resistant to MK-2206 compared to cells expressing control non-specific shRNA. These results suggest that AKT phosphatase activity in AML may affect response to MK-2206. A recent study in liver cancer demonstrated that MK-2206 synergized with the multi-kinase inhibitor Sorafenib. Since Sorafenib targets the Fms-like tyrosine kinase 3 (FLT3) and mutations that activate the kinase in AML confer poor prognosis, we examined if MK-2206 could synergize with Sorafenib to kill leukemia cells with mutation of FLT3 internal tandem duplication (ITD) mutation. The combination of MK-2206 and Sorafenib was effective at killing MOLM13 cells and AML blast cells with the FLT3-ITD. Taken together, these findings suggest that MK-2206 may be effective to block AKT signaling pathways and could be beneficial as a therapeutic agent perhaps as a single agent or in combination with a drug such as Sorafenib in the therapy of AML.

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 3659. doi:1538-7445.AM2012-3659