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|Ref Type||Journal Article|
|Authors||Qiao X, Ma J, Knight T, Su Y, Edwards H, Polin L, Li J, Kushner J, Dzinic SH, White K, Wang J, Lin H, Wang Y, Wang L, Wang G, Taub JW, Ge Y|
|Title||The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML.|
|Journal||Blood cancer journal|
|Date||2021 Jun 07|
|Abstract Text||About 25% of patients with acute myeloid leukemia (AML) harbor FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (ITD) mutations and their prognosis remains poor. Gilteritinib is a FLT3 inhibitor approved by the US FDA for use in adult FLT3-mutated relapsed or refractory AML patients. Monotherapy, while efficacious, shows short-lived responses, highlighting the need for combination therapies. Here we show that gilteritinib and CUDC-907, a dual inhibitor of PI3K and histone deacetylases, synergistically induce apoptosis in FLT3-ITD AML cell lines and primary patient samples and have striking in vivo efficacy. Upregulation of FLT3 and activation of ERK are mechanisms of resistance to gilteritinib, while activation of JAK2/STAT5 is a mechanism of resistance to CUDC-907. Gilteritinib and CUDC-907 reciprocally overcome these mechanisms of resistance. In addition, the combined treatment results in cooperative downregulation of cellular metabolites and persisting antileukemic effects. CUDC-907 plus gilteritinib shows synergistic antileukemic activity against FLT3-ITD AML in vitro and in vivo, demonstrating strong translational therapeutic potential.|
|Molecular Profile||Treatment Approach|
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|Therapy Name||Drugs||Efficacy Evidence||Clinical Trials|
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|FLT3 exon 14 ins||acute myeloid leukemia||sensitive||CUDC-907 + Gilteritinib||Preclinical - Cell line xenograft||Actionable||In a preclinical study, the combination of CUDC-907 (fimepinostat) and Xospata (gilteritinib) synergistically inhibited cell growth, decreased Flt3 signaling, and induced apoptosis in patient-derived acute myeloid leukemia cells harboring FLT3-ITD mutations in culture, and resulted in prolonged survival compared to either agent alone in cell line xenograft models (PMID: 34099621).||34099621|
|FLT3 exon 14 ins||acute myeloid leukemia||sensitive||AZD1480 + CUDC-907||Preclinical - Cell culture||Actionable||In a preclinical study, the combination of CUDC-907 (fimepinostat) and AZD1480 inhibited phosphorylation of Stat5 and induced apoptosis in acute myeloid leukemia cell lines harboring FLT3-ITD mutations in culture, and demonstrated improved activity over either agent alone (PMID: 34099621).||34099621|