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

• Published in: Biochemical pharmacology Vol. 87; no. 2; pp. 284 - 291
• Main Authors: Eriksson, Anna, Kalushkova, Antonia, Jarvius, Malin, Hilhorst, Riet, Rickardson, Linda, Kultima, Hanna Göransson, de Wijn, Rik, Hovestad, Liesbeth, Fryknäs, Mårten, Öberg, Fredrik, Larsson, Rolf, Parrow, Vendela, Höglund, Martin
• Format: Journal Article
• Language: English
• Published: England Elsevier Inc 15.01.2014
• Subjects: Acute myeloid leukemia; AKN-028; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; Cell Cycle Checkpoints - drug effects; Cell Cycle Checkpoints - genetics; Dose-Response Relationship, Drug; Down-Regulation - drug effects; Down-Regulation - genetics; Genes, myc - drug effects; Genes, myc - genetics; HL-60 Cells; Humans; Indoles - pharmacology; Indoles - therapeutic use; Leukemia, Myeloid, Acute - enzymology; Leukemia, Myeloid, Acute - genetics; Leukemia, Myeloid, Acute - pathology; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Protein-Tyrosine Kinases - antagonists & inhibitors; Protein-Tyrosine Kinases - metabolism; Pyrazines - pharmacology; Pyrazines - therapeutic use; Signal transduction; Tumor Cells, Cultured; Tyrosine kinase inhibitor; Signal transduction; Tyrosine kinase inhibitor; Acute myeloid leukemia; AKN-028
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/j.bcp.2013.10.022

Significantly altered gene expression induced by AKN-028 compared to reference compound midostaurin or vehicle control in 3 different AML cell types, displayed as a principle component analysis plot. 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 G0/1 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.