Effect of inhibiting Pim-1 kinase in acute myeloid leukemia with FLT3 internal tandem duplication

Abstract

The project is focused on combinatorial treatment involving downstream inhibitors of FLT3 signaling, representing a promising approach for treating AML patients with FLT3-ITD. Pim-1 kinase is upregulated downstream of FLT3-ITD pathway by a positive feedback loop. The goal of this work was to characterize Pim kinase inhibitor (PIM447, currently in clinical trials) sensitization of cells FLT3-ITD to apoptosis induction by combination of FLT3 inhibitors and chemotherapy drugs. PIM447 sensitizes FLT3-ITD cells to FLT3 inhibitors and topoisomerase-2 inhibitors. Co-treatment with the Pim kinase inhibitor AZD1208 and FLT3 inhibitor quizartinib was found to enhance apoptosis of cells FLT3-ITD post-translationally, decreasing expression of the anti-apoptotic protein Mcl-1 through increased proteasomal degradation and in association with decreased expression of deubiquitinase USP9X. PIM447 in combination with FLT3 inhibitors as quizartinib, sorafenib and midostaurin and topoisomerase-2 inhibitors as daunorubicin, mitoxantrone and etoposide in FLT3-ITD cells, induced a dose response dependent increasing apoptosis.