The combination of CUDC-907 and gilteritinib shows promising in vitro and in vivo antileukemic activity against FLT3-ITD AML
Open Access
- 7 June 2021
- journal article
- research article
- Published by Springer Science and Business Media LLC in Blood Cancer Journal
- Vol. 11 (6), 1-17
- https://doi.org/10.1038/s41408-021-00502-7
Abstract
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.Keywords
Funding Information
- Ashok & Ingrid Sarnaik Endowment for Resident and Fellow Research
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (P30 CA022453)
- Decerchio/Guisewite Family, Justin’s Gift, Elana Fund, Ginopolis/Karmanos Endowment, Ring Screw Textron Endowed Chair for Pediatric Cancer Research
- The Children’s Foundation, U Can Cer Vive Foundation, and Kids Without Cancer
This publication has 54 references indexed in Scilit:
- Panobinostat Enhances Cytarabine and Daunorubicin Sensitivities in AML Cells through Suppressing the Expression of BRCA1, CHK1, and Rad51PLOS ONE, 2013
- How I treat pediatric acute myeloid leukemiaBlood, 2012
- Axl-dependent signalling: a clinical updateClinical Science, 2011
- Mechanisms of Synergistic Antileukemic Interactions between Valproic Acid and Cytarabine in Pediatric Acute Myeloid LeukemiaClinical Cancer Research, 2010
- Ubiquitin conjugase UBCH8 targets active FMS-like tyrosine kinase 3 for proteasomal degradationLeukemia, 2010
- FLT3-ITD up-regulates MCL-1 to promote survival of stem cells in acute myeloid leukemia via FLT3-ITD–specific STAT5 activationBlood, 2009
- Bim Upregulation by Histone Deacetylase Inhibitors Mediates Interactions with the Bcl-2 Antagonist ABT-737: Evidence for Distinct Roles for Bcl-2, Bcl-xL, and Mcl-1Molecular and Cellular Biology, 2009
- c-Myc suppression of miR-23a/b enhances mitochondrial glutaminase expression and glutamine metabolismNature, 2009
- Myc regulates a transcriptional program that stimulates mitochondrial glutaminolysis and leads to glutamine addictionProceedings of the National Academy of Sciences of the United States of America, 2008
- Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT MethodMethods, 2001