PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways

PIM kinases (PIM1, 2 and 3) are involved in cell proliferation and survival signalling and are emerging targets for the therapy of various malignancies. We found that a significant proportion of primary acute myeloid leukaemia (AML) samples showed PIM1 and PIM2 expression by quantitative reverse transcription polymerase chain reaction. Therefore, we investigated the effects of a novel ATP-competitive pan-PIM inhibitor, AZD1897, on AML cell growth and survival. PIM inhibition showed limited single agent activity in AML cell lines and primary AML cells, including those with or without FLT3-internal tandem duplication (ITD) mutation. However, significant synergy was seen when AZD1897 was combined with the Akt inhibitor AZD5363, a compound that is in early-phase clinical trials. AML cells from putative leukaemia stem cell subsets, including CD34+38- and CD34+38+ fractions, were equivalently affected by dual PIM/Akt inhibition when compared with bulk tumour cells. Analysis of downstream signalling pathways showed that combined PIM/Akt inhibition downregulated mTOR outputs (phosphorylation of 4EBP1 and S6) and markedly reduced levels of the anti-apoptotic protein MCL1. The combination of PIM and Akt inhibition holds promise for the treatment of AML.