title: AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and dose dependent reduction of tyrosine kinase activity in acute myeloid leukemia.
abstract: 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.
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden. Electronic address: anna.eriksson@medsci.uu.se.
authors.forename: Anna
authors.initials: A
authors.lastname: Eriksson
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Antonia
authors.initials: A
authors.lastname: Kalushkova
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Malin
authors.initials: M
authors.lastname: Jarvius
authors.affiliation: PamGene International B.V., 's-Hertogenbosch, The Netherlands.
authors.forename: Riet
authors.initials: R
authors.lastname: Hilhorst
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Linda
authors.initials: L
authors.lastname: Rickardson
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Hanna Göransson
authors.initials: HG
authors.lastname: Kultima
authors.affiliation: PamGene International B.V., 's-Hertogenbosch, The Netherlands.
authors.forename: Rik
authors.initials: R
authors.lastname: de Wijn
authors.affiliation: PamGene International B.V., 's-Hertogenbosch, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Hovestad
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Mårten
authors.initials: M
authors.lastname: Fryknäs
authors.affiliation: Department of Immunology, Genetics and Pathology, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Öberg
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Rolf
authors.initials: R
authors.lastname: Larsson
authors.affiliation: Akinion Pharmaceuticals AB, SE-17177 Stockholm, Sweden.
authors.forename: Vendela
authors.initials: V
authors.lastname: Parrow
authors.affiliation: Department of Medical Sciences, Uppsala University, SE-751 85 Uppsala, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Höglund
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D059447:Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects* / Q000235:genetics; D016259:Genes, myc / Q000187:drug effects* / Q000235:genetics; D018922:HL-60 Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology* / Q000627:therapeutic use; D015470:Leukemia, Myeloid, Acute / Q000201:enzymology / Q000235:genetics* / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000090063:Proto-Oncogene Mas; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D007211:Indoles; C000715470:MAS1 protein, human; C587069:N-3-(1H-indol-5-yl)-5-pyridin-4-yl-pyrazine-2,3-diamine; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011719:Pyrazines; D011505:Protein-Tyrosine Kinases
keywords: AKN-028; Acute myeloid leukemia; Signal transduction; Tyrosine kinase inhibitor