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|Ref Type||Journal Article|
|Authors||Meja K, Stengel C, Sellar R, Huszar D, Davies BR, Gale RE, Linch DC, Khwaja A|
|Title||PIM and AKT kinase inhibitors show synergistic cytotoxicity in acute myeloid leukaemia that is associated with convergence on mTOR and MCL1 pathways.|
|Journal||British journal of haematology|
|Abstract Text||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.|
|Molecular Profile||Treatment Approach|
|Gene Name||Source||Synonyms||Protein Domains||Gene Description||Gene Role|
|Drug Name||Trade Name||Synonyms||Drug Classes||Drug Description|
|AZD1897||PIM Inhibitor (Pan) 9||AZD1897 is an ATP-competitive inhibitor of PIM kinases 1, 2, and 3, which may result in decreased cell proliferation (PMID: 24975213).|
|Gene||Variant||Impact||Protein Effect||Variant Description||Associated with drug Resistance|
|Molecular Profile||Indication/Tumor Type||Response Type||Therapy Name||Approval Status||Evidence Type||Efficacy Evidence||References|
|Unknown unknown||acute myeloid leukemia||not applicable||AZD1897 + Capivasertib||Preclinical||Actionable||In a preclinical study, acute myeloid leukemia cells treated with the combination of AZD1897 and AZD5363 produced a synergistic effect, resulting in decreased cell survival (PMID: 24975213).||24975213|