AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and dose dependent reduction of tyrosine kinase activity in acute myeloid leukemia

作者：Eriksson Anna^*; Kalushkova Antonia; Jarvius Malin; Hilhorst Riet; Rickardson Linda; Kultima Hanna Goransson; de Wijn Rik; Hovestad Lie**eth; Fryknas Marten; Oberg Fredrik; Larsson Rolf; Parrow Vendela; Hoglund Martin

来源：Biochemical Pharmacology, 2014, 87(2): 284-291.

DOI：10.1016/j.bcp.2013.10.022

• Acute myeloid leukemia
• AKN-028
• Tyrosine kinase inhibitor
• Signal transduction

AKN-028 is a novel tyrosine kinase inhibitor with preclinical activity in acute myeloid leukemia (AML), presently undergoing investigation in a phase I/II study. It is a potent inhibitor of the FMS-like kinase 3 (FLT3) but shows in vitro activity in a wide range of AML samples. In the present study, we have characterized the effects of AKN-028 on AML cells in more detail. AKN-028 induced a dose-dependent G(0)/arrest in AML cell line MV4-11. Treatment with AKN-028 caused significantly altered gene expression in all AML cell types tested (430 downregulated, 280 upregulated transcripts). Subsequent gene set enrichment analysis revealed enrichment of genes associated with the proto-oncogene and cell cycle regulator c-Myc among the downregulated genes in both AKN-028 and midostaurin treated cells. Kinase activity profiling in AML cell lines and primary AML samples showed that tyrosine kinase activity, but not serine/threonine kinase activity, was inhibited by AKN-028 in a dose dependent manner in all samples tested, reaching approximately the same level of kinase activity. Cells sensitive to AKN-028 showed a higher overall tyrosine kinase activity than more resistant ones, whereas serine/threonine kinase activity was similar for all primary AML samples.
In summary, AKN-028 induces cell cycle arrest in AML cells, downregulates Myc-associated genes and affect several signaling pathways. AML cells with high global tyrosine kinase activity seem to be more sensitive to the cytotoxic effect of AKN-028 in vitro.

• 出版日期2014-1-15