ArticleEBioMedicine2019
The BET inhibitor JQ1 attenuates double-strand break repair and sensitizes models of pancreatic ductal adenocarcinoma to PARP inhibitors.
Article in EBioMedicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.
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Who cites it
66 citing papers in PubMed, 103 citations in OpenAlex.
- JPI-547, a novel dual inhibitor of PARP1/2 and tankyrase is more effective than first-generation PARP inhibitors in preclinical BRCA1/2-mutated cancer models.British journal of cancer · 2026Article
- MicroRNA-based strategies to overcome the immunotherapy barrier in pancreatic ductal adenocarcinoma.Frontiers in immunology · 2026Review
- Identification of BET inhibitors (BETi) against solitary fibrous tumor (SFT) through high-throughput screening (HTS).Neoplasia (New York, N.Y.) · 2025Article
- Long non-coding RNAs: Emerging regulators of invasion and metastasis in pancreatic cancer.Journal of advanced research · 2025Review
- GX15-070 enhances niraparib efficacy in ovarian cancer by promoting a shift in Mcl1-mediated DNA repair pathway from HR to NHEJ.Journal of translational medicine · 2025Article
- Synergistic enhancement of PARP inhibition via small molecule UNI66-mediated suppression of BRD4-dependent transcription ofNAR cancer · 2025Article
- Evaluating TcAs for Use in Biotechnology Applications.Biotech (Basel (Switzerland)) · 2025Article
- Super-enhancers in tumors: unraveling recent advances in their role in Oncogenesis and the emergence of targeted therapies.Journal of translational medicine · 2025Review
- Article
- Sequential Inhibition of PARP and BET as a Rational Therapeutic Strategy for Glioblastoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- A high-throughput approach to identify BRCA1-downregulating compounds to enhance PARP inhibitor sensitivity.iScience · 2024Article
- BET inhibition decreases HMGCS2 and sensitizes resistant pancreatic tumors to gemcitabine.Cancer letters · 2024Article
- Targeting BRD4: Potential therapeutic strategy for head and neck squamous cell carcinoma (Review).Oncology reports · 2024Article
- The BET inhibitor sensitivity is associated with the expression level of CDC25B in pancreatic cancer models.Cancer drug resistance (Alhambra, Calif.) · 2024Article
- Bromodomain and extraterminal (BET) proteins: biological functions, diseases, and targeted therapy.Signal transduction and targeted therapy · 2023Review
- KLF5 Promotes Tumor Progression and Parp Inhibitor Resistance in Ovarian Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2023Article
- First-in-human Study of AZD5153, A Small-molecule Inhibitor of Bromodomain Protein 4, in Patients with Relapsed/Refractory Malignant Solid Tumors and Lymphoma.Molecular cancer therapeutics · 2023Article
- A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer.Cell death & disease · 2023Article
- YAP/BRD4-controlled ROR1 promotes tumor-initiating cells and hyperproliferation in pancreatic cancer.The EMBO journal · 2023Article
- Synergistic effect of PARP inhibitor and BRD4 inhibitor in multiple models of ovarian cancer.Journal of cellular and molecular medicine · 2023Article
6 more citing papers are in PubMed but not listed here.
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Authors and funding
9 authors at 3 institutions in 1 country.
Funding
Abstract
backgroundDNA repair deficiency accumulates DNA damage and sensitizes tumor cells to PARP inhibitors (PARPi). Based on our observation that the BET inhibitor JQ1 increases levels of DNA damage, we evaluated the efficacy of JQ1 + the PARPi olaparib in preclinical models of pancreatic ductal adenocarcinoma (PDAC). We also addressed the mechanism by which JQ1 increased DNA damage.
methodsThe effect of JQ1 + olaparib on in vivo tumor growth was assessed with patient-derived xenograft (PDX) models of PDAC. Changes in protein expression were detected by immunohistochemistry and immunoblot. In vitro growth inhibition and mechanistic studies were done using alamarBlue, qRT-PCR, immunoblot, immunofluorescence, ChIP, and shRNA knockdown assays.
findingsTumors exposed in vivo to JQ1 had higher levels of the DNA damage marker γH2AX than tumors exposed to vehicle only. Increases in γH2AX was concomitant with decreased expression of DNA repair proteins Ku80 and RAD51. JQ1 + olaparib inhibited the growth of PDX tumors greater than either drug alone. Mechanistically, ChIP assays demonstrated that JQ1 decreased the association of BRD4 and BRD2 with promoter loci of Ku80 and RAD51, and shRNA data showed that expression of Ku80 and RAD51 was BRD4- and BRD2-dependent in PDAC cell lines.
interpretationThe data are consistent with the hypothesis that JQ1 confers a repair deficient phenotype and the consequent accumulation of DNA damage sensitizes PDAC cells to PARPi. Combinations of BET inhibitors with PARPi may provide a novel strategy for treating PDAC. FUND: NIH grants R01CA208272 and R21CA205501; UAB CMB T32 predoctoral training grant.
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Registered trials
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.