title: PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways.
abstract: 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.
authors: Department of Haematology, University College London Cancer Institute, London, UK.
authors: Koremu
authors: K
authors: Meja
authors: Chloe
authors: C
authors: Stengel
authors: Rob
authors: R
authors: Sellar
authors: Dennis
authors: D
authors: Huszar
authors: Barry R
authors: BR
authors: Davies
authors: Rosemary E
authors: RE
authors: Gale
authors: David C
authors: DC
authors: Linch
authors: Asim
authors: A
authors: Khwaja
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use / Q000633:toxicity; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D015870:Gene Expression; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D009154:Mutation; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use / Q000633:toxicity*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000235:genetics; D051573:Proto-Oncogene Proteins c-pim-1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D055815:Young Adult
chemical_list: D000970:Antineoplastic Agents; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D051573:Proto-Oncogene Proteins c-pim-1; D058570:TOR Serine-Threonine Kinases; C406031:proto-oncogene proteins pim
keywords: apoptosis; kinase; leukaemia; oncogenes; therapy