Targeting multiple signal pathways simultaneously might provide effective therapeutic strategies in acute myeloid leukemia.

6546 Background: MEK/MAPK and PI3K/Akt pathways have been demonstrated to be constitutively activated in the majority of AML patients and associated with poor prognosis, but inhibition of single pathway has only demonstrated modest clinical activity. Methods: The current study evaluated the efficacy of combination of orally available inhibitors to MEK (AZD6244, Astra Zeneca), PI3K/mTOR (NVP-BEZ235, Novartis), Akt (MK 2206, Merck) and Bcl-2 family members (ABT263, Abbott) in human AML cell lines and primary AML patient samples. Results: In MV 4;11 cells (harboring both MLL re-arrangement and FLT3-ITD mutation), AZD6244 or BEZ235 alone moderately decreased viable cells by 30-40%, but combination of these two had dramatic additive effect of cell killing by 70-80%. ABT263 plus AZD6244 or BEZ235 resulted in further additive cell killing effects. While MK2206 alone had little effect, combination of MK2206 with AZD6244 resulted in excellent synergy. Similar effects were observed in HL60 cells with complex karyot...