PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways. (30th June 2014)

• Record Type: Journal Article
• Authors: Meja, Koremu; Stengel, Chloe; Sellar, Rob; Huszar, Dennis; Davies, Barry R.; Gale, Rosemary E.; Linch, David C.; Khwaja, Asim
• Is Part Of: British journal of haematology. Volume 167:Number 1(2014:Oct.)
• Page Start: 69
• Page End: 79
• Publication Date: 2014-06-30
• Subjects: Hematology -- Periodicals; Blood -- Diseases -- Periodicals; 616.15
• DOI: 10.1111/bjh.13013
• Languages: English
• ISSNs: 0007-1048

Abstract

<abstract abstract-type="main" id="bjh13013-abs-0001"> <title>Summary</title> <p>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 <italic>PIM1</italic> and <italic>PIM2</italic> 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 <italic>FLT3</italic>‐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.</p> </abstract>