AKN-028 induces cell cycle arrest, downregulation of Myc associated genes and dose dependent reduction of tyrosine kinase activity in acute myeloid leukemia
Anna Eriksson, Antonia Kalushkova, Malin Jarvius, Riet Hilhorst, Linda Rickardson, Hanna Göransson Kultima, Rik de Wijn, Liesbeth Hovestad, Mårten Fryknäs, Fredrik Öberg, Rolf Larsson, Vendela Parrow, Martin Höglund, Anna Eriksson, Antonia Kalushkova, Malin Jarvius, Riet Hilhorst, Linda Rickardson, Hanna Göransson Kultima, Rik de Wijn, Liesbeth Hovestad, Mårten Fryknäs, Fredrik Öberg, Rolf Larsson, Vendela Parrow, Martin Höglund
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.
Trial registration: ClinicalTrials.gov NCT01573247.
Keywords: AKN-028; Acute myeloid leukemia; Signal transduction; Tyrosine kinase inhibitor.
Copyright © 2013 The Authors. Published by Elsevier Inc. All rights reserved.
Source: PubMed