ArticleJournal for immunotherapy of cancer2023
BRD4 inhibition impairs DNA mismatch repair, induces mismatch repair mutation signatures and creates therapeutic vulnerability to immune checkpoint blockade in MMR-proficient tumors.
Article in Journal for immunotherapy of cancer, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers.
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Who cites it
13 citing papers in PubMed, 16 citations in OpenAlex.
- Targeting the DNA Damage Response in Cancer.MedComm · 2026Review
- DNA Repair, Epigenetic Dysregulation, and Cytokine Network Crosstalk in Head and Neck Cancer: Emerging Therapeutic Opportunities and Clinical Trials.Current oncology reports · 2026Review
- Mechanistic role of GNE-987 targeting BRD4-HCP5 axis in pediatric T-cell acute lymphoblastic leukemia.Journal of cell communication and signaling · 2026Article
- MYC at the tumor-immune interface: mechanisms of immune escape and immunotherapy resistance.Frontiers in immunology · 2026Review
- PROTAC-loaded nanocapsules degrading BRD4 for radio-chemotherapy sensitization in glioblastoma.Acta pharmaceutica Sinica. B · 2025Article
- SET facilitates immune escape of microsatellite stability colorectal cancer by inhibiting c-Myc degradation.Cancer science · 2025Article
- Characterization of lysine crotonylation-related lncRNAs for prognostic assessment and immune response in glioma.Frontiers in pharmacology · 2025Article
- Targeted Drug Nanodelivery and Immunotherapy for Combating Tumor Resistance.Combinatorial chemistry & high throughput screening · 2025Review
- Review
- BRD2 promotes antibody class switch recombination by facilitating DNA repair in collaboration with NIPBL.Nucleic acids research · 2024Article
- Epigenetic MLH1 silencing concurs with mismatch repair deficiency in sporadic, naturally occurring colorectal cancer in rhesus macaques.Journal of translational medicine · 2024Article
- Article
- Targeting super-enhancer activity for colorectal cancer therapy.American journal of translational research · 2024Review
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Authors and funding
21 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
backgroundMismatch repair deficiency (dMMR) is a well-recognized biomarker for response to immune checkpoint blockade (ICB). Strategies to convert MMR-proficient (pMMR) to dMMR phenotype with the goal of sensitizing tumors to ICB are highly sought. The combination of bromodomain containing 4 (BRD4) inhibition and ICB provides a promising antitumor effect. However, the mechanisms underlying remain unknown. Here, we identify that BRD4 inhibition induces a persistent dMMR phenotype in cancers.
methodsWe confirmed the correlation between BRD4 and mismatch repair (MMR) by the bioinformatic analysis on The Cancer Genome Atlas and Clinical Proteomic Tumor Analysis Consortium data, and the statistical analysis on immunohistochemistry (IHC) scores of ovarian cancer specimens. The MMR genes (MLH1,MSH2,MSH6,PMS2) were measured by quantitative reverse transcription PCR, western blot, and IHC. The MMR status was confirmed by whole exome sequencing, RNA sequencing, MMR assay and hypoxanthine-guanine phosphoribosyl transferase gene mutation assay. The BRD4i AZD5153 resistant models were induced both in vitro and in vivo. The transcriptional effects of BRD4 on MMR genes were investigated by chromatin immunoprecipitation among cell lines and data from the Cistrome Data Browser. The therapeutic response to ICB was testified in vivo. The tumor immune microenvironment markers, such as CD4, CD8, TIM-3, FOXP3, were measured by flow cytometry.
resultsWe identified the positive correlation between
conclusionsWe demonstrated that BRD4 inhibition suppressed expression of genes critical to MMR, dampened MMR, and increased dMMR mutation signatures both in vitro and in vivo, sensitizing pMMR tumors to ICB. Importantly, even in BRD4 inhibitors (BRD4i)-resistant tumor models, the effects of BRD4i on MMR function were maintained rendering tumors sensitive to ICB. Together, these data identified a strategy to induce dMMR in pMMR tumors and further, indicated that BRD4i sensitive and resistant tumors could benefit from immunotherapy.
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