ArticleMolecular cancer therapeutics2014
BET protein antagonist JQ1 is synergistically lethal with FLT3 tyrosine kinase inhibitor (TKI) and overcomes resistance to FLT3-TKI in AML cells expressing FLT-ITD.
Article in Molecular cancer therapeutics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 95 papers.
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Who cites it
95 citing papers in PubMed, 137 citations in OpenAlex.
- Structural Basis for BD1-Preferring 2,4-Disubstituted Pyrimidine BRDT Inhibitors.Journal of medicinal chemistry · 2026Article
- Counter-Therapeutic Strategies for Resistance of FLT3 Inhibitors in Acute Myeloid Leukemia.Cells · 2025Review
- Development and comparison of single FLT3-inhibitors to dual FLT3/TAF1-inhibitors as an anti-leukemic approach.PloS one · 2025Article
- Lactate Utilization Enables Metabolic Escape to Confer Resistance to BET Inhibition in Acute Myeloid Leukemia.Cancer research · 2024Article
- The multi-CDK inhibitor dinaciclib reverses bromo- and extra-terminal domain (BET) inhibitor resistance in acute myeloid leukemia via inhibition of Wnt/β-catenin signaling.Experimental hematology & oncology · 2024Article
- BET in hematologic tumors: Immunity, pathogenesis, clinical trials and drug combinations.Genes & diseases · 2023Review
- Targeting BET Proteins Downregulates miR-33a To Promote Synergy with PIM Inhibitors in CMML.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023Article
- ACC010, a novel BRD4 inhibitor, synergized with homoharringtonine in acute myeloid leukemia with FLT3-ITD.Molecular oncology · 2023Article
- Azacitidine Is Synergistically Lethal with XPO1 Inhibitor Selinexor in Acute Myeloid Leukemia by Targeting XPO1/eIF4E/c-MYC Signaling.International journal of molecular sciences · 2023Article
- BET Bromodomain Inhibitors: Novel Design Strategies and Therapeutic Applications.Molecules (Basel, Switzerland) · 2023Review
- MicroRNA profiling of paediatric AML withOncology reports · 2022Article
- Super enhancers: Pathogenic roles and potential therapeutic targets for acute myeloid leukemia (AML).Genes & diseases · 2022Review
- Epigenetic Alterations and Inflammation as Emerging Use for the Advancement of Treatment in Non-Small Cell Lung Cancer.Frontiers in immunology · 2022Review
- Functional Evaluation of KEL as an Oncogenic Gene in the Progression of Acute Erythroleukemia.Oxidative medicine and cellular longevity · 2022Article
- The BET bromodomain inhibitor ZEN-3365 targets the Hedgehog signaling pathway in acute myeloid leukemia.Annals of hematology · 2021Article
- BET Proteins as Attractive Targets for Cancer Therapeutics.International journal of molecular sciences · 2021Review
- Novel Therapies in Myeloproliferative Neoplasms: Beyond JAK Inhibitor Monotherapy.Journal of immunotherapy and precision oncology · 2021Review
- Chemogenomics for drug discovery: clinical molecules from open access chemical probes.RSC chemical biology · 2021Review
- Superior efficacy of co-targeting GFI1/KDM1A and BRD4 against AML and post-MPN secondary AML cells.Blood cancer journal · 2021Article
- A novel combination regimen of BET and FLT3 inhibition for FLT3-ITD acute myeloid leukemia.Haematologica · 2021Article
35 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 2 institutions in 1 country.
Funding
Abstract
Recently, treatment with bromodomain and extraterminal protein antagonist (BA) such as JQ1 has been shown to inhibit growth and induce apoptosis of human acute myelogenous leukemia (AML) cells, including those expressing FLT3-ITD. Here, we demonstrate that cotreatment with JQ1 and the FLT3 tyrosine kinase inhibitor (TKI) ponatinib or AC220 synergistically induce apoptosis of cultured and primary CD34(+) human AML blast progenitor cells (BPC) expressing FLT3-ITD. Concomitantly, as compared with each agent alone, cotreatment with JQ1 and the FLT3-TKI caused greater attenuation of c-MYC, BCL2, and CDK4/6. Simultaneously, cotreatment with JQ1 and the FLT3-TKI increased the levels of p21, BIM, and cleaved PARP, as well as mediated marked attenuation of p-STAT5, p-AKT, and p-ERK1/2 levels in AML BPCs. Conversely, cotreatment with JQ1 and FLT3-TKI was significantly less active against CD34(+) normal bone marrow progenitor cells. Knockdown of BRD4 by short hairpin RNA also sensitized AML cells to FLT3-TKI. JQ1 treatment induced apoptosis of mouse Ba/F3 cells ectopically expressing FLT3-ITD with or without FLT3-TKI-resistant mutations F691L and D835V. Compared with the parental human AML FLT3-ITD-expressing MOLM13, MOLM13-TKIR cells resistant to AC220 were markedly more sensitive to JQ1-induced apoptosis. Furthermore, cotreatment with JQ1 and the pan-histone deacetylase inhibitor (HDI) panobinostat synergistically induced apoptosis of FLT3-TKI-resistant MOLM13-TKIR and MV4-11-TKIR cells. Collectively, these findings support the rationale for determining the in vivo activity of combined therapy with BA and FLT3-TKI against human AML cells expressing FLT3-ITD or with BA and HDI against AML cells resistant to FLT3-TKI.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.