Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Shivani KapoorMaria R Baer

Abstract

Purpose:fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) is present in 30% of acute myeloid leukemia (AML), and these patients have short disease-free survival. FLT3 inhibitors have limited and transient clinical activity, and concurrent treatment with inhibitors of parallel or downstream signaling may improve responses. The oncogenic serine/threonine kinase Pim-1 is upregulated downstream of FLT3-ITD and also promotes its signaling in a positive feedback loop, suggesting benefit of combined Pim and FLT3 inhibition.Experimental Design: Combinations of clinically active Pim and FLT3 inhibitors were studied in vitro and in vivoResults: Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated in vitro growth of FLT3-ITD, but not wild-type FLT3 (FLT3-WT), cell lines. AZD1208 cotreatment increased FLT3 inhibitor-induced apoptosis of FLT3-ITD, but not FLT3-WT, cells measured by sub-G1 fraction, annexin V labeling, mitochondrial membrane potential, and PARP and caspase-3 cleavage. Concurrent treatment with AZD1208 and the FLT3 inhibitor quizartinib decreased growth of MV4-11 cells, with FLT3-ITD, in mouse xenografts, and prolonged survival, enhanced ...Continue Reading

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Citations

Feb 26, 2019·Therapeutic Advances in Hematology·Nicholas J ShortNaval Daver
Aug 28, 2020·Frontiers in Genetics·Jinxin DongXiguo Yuan
Feb 6, 2020·Cancer Discovery·Nicholas J ShortNaval Daver
Sep 5, 2019·Molecular Cancer Therapeutics·Bandish B Kapadia, Ronald B Gartenhaus
Dec 12, 2020·Molecular Cancer Therapeutics·Rachel K Toth, Noel A Warfel
Jan 12, 2021·Frontiers in Oncology·Vanessa E Kennedy, Catherine C Smith
Mar 7, 2020·Trends in Immunology·Blanca T Gutierrez-DiazPanagiotis Ntziachristos
Mar 30, 2021·Molecular Pharmaceutics·Pratheppa RajagopalUma Maheswari Krishnan

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