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• W4361952023 abstract "<div>Abstract<p><b>Purpose:</b> <i>fms</i>-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.</p><p><b>Experimental Design:</b> Combinations of clinically active Pim and FLT3 inhibitors were studied <i>in vitro</i> and <i>in vivo</i>.</p><p><b>Results:</b> Concurrent treatment with the pan-Pim inhibitor AZD1208 and FLT3 inhibitors at clinically applicable concentrations abrogated <i>in vitro</i> 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 apoptosis of FLT3-ITD primary AML blasts, but not FLT3-WT blasts or remission marrow cells, and decreased FLT3-ITD AML blast colony formation. Mechanistically, AZD1208 and quizartinib cotreatment decreased expression of the antiapoptotic protein Mcl-1. Decrease in Mcl-1 protein expression was abrogated by treatment with the proteasome inhibitor MG132, and was preceded by downregulation of the Mcl-1 deubiquitinase USP9X, a novel mechanism of Mcl-1 regulation in AML.</p><p><b>Conclusions:</b> The data support clinical testing of Pim and FLT3 inhibitor combination therapy for FLT3-ITD AML. <i>Clin Cancer Res; 24(1); 234–47. ©2017 AACR</i>.</p></div>" @default.
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• W4361952023 date "2023-03-31" @default.
• W4361952023 modified "2023-09-26" @default.
• W4361952023 title "Data from Concurrent Inhibition of Pim and FLT3 Kinases Enhances Apoptosis of FLT3-ITD Acute Myeloid Leukemia Cells through Increased Mcl-1 Proteasomal Degradation" @default.
• W4361952023 doi "https://doi.org/10.1158/1078-0432.c.6525348.v1" @default.
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