ArticleCell cycle (Georgetown, Tex.)2011
Selective radiosensitization of p53 mutant pancreatic cancer cells by combined inhibition of Chk1 and PARP1.
Article in Cell cycle (Georgetown, Tex.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 92 citations in OpenAlex.
- Comparing and combining xevinapant with ATR and PARP inhibition for the radiosensitization of HPV-negative HNSCC cells.Scientific reports · 2026Article
- Radiogenomics and the DNA damage response: opportunities for biomarker-guided radiosensitization in pancreatic cancer.Frontiers in oncology · 2026Review
- Bibliometric analysis of olaparib and pancreatic cancer from 2009 to 2022: A global perspective.World journal of gastrointestinal oncology · 2024Article
- DDB2 expression lights the way for precision radiotherapy response in PDAC cells, with or without olaparib.Cell death discovery · 2024Article
- PARP-1 selectively impairsGut · 2024Article
- The Potential for Targeting GCancers · 2024Review
- Novel Cellular Functions of ATR for Therapeutic Targeting: Embryogenesis to Tumorigenesis.International journal of molecular sciences · 2023Review
- Impaired DNA double-strand break repair and effective radiosensitization of HPV-negative HNSCC cell lines through combined inhibition of PARP and Wee1.Clinical and translational radiation oncology · 2023Article
- Targeting K-Ras-mediated DNA damage response in radiation oncology: Current status, challenges and future perspectives.Clinical and translational radiation oncology · 2023Review
- Polyadenosine diphosphate-ribose polymerase inhibitors: advances, implications, and challenges in tumor radiotherapy sensitization.Frontiers in oncology · 2023Review
- Natural products targeting the ATR-CHK1 signaling pathway in cancer therapy.Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie · 2022Review
- Advanced Strategies for Therapeutic Targeting of Wild-Type and Mutant p53 in Cancer.Biomolecules · 2022Review
- Radiotherapy as a tool to elicit clinically actionable signalling pathways in cancer.Nature reviews. Clinical oncology · 2022Review
- DDRugging glioblastoma: understanding and targeting the DNA damage response to improve future therapies.Molecular oncology · 2022Review
- Gemcitabine-Based Chemoradiotherapy Enhanced by a PARP Inhibitor in Pancreatic Cancer Cell Lines.International journal of molecular sciences · 2021Article
- Potential Molecular Targets in the Setting of Chemoradiation for Esophageal Malignancies.Journal of the National Cancer Institute · 2021Review
- Inhibitors of Nucleotide Excision Repair Decrease UVB-Induced Mutagenesis-An In Vitro Study.International journal of molecular sciences · 2021Article
- Combinatorial Efficacy of Olaparib with Radiation and ATR Inhibitor Requires PARP1 Protein in Homologous Recombination-Proficient Pancreatic Cancer.Molecular cancer therapeutics · 2021Article
- Dual Inhibition of PARP and the Intra-S/G2 Cell Cycle Checkpoints Results in Highly Effective Radiosensitization of HPV-Positive HNSCC Cells.Frontiers in oncology · 2021Article
- PARP Inhibition Increases the Reliance on ATR/CHK1 Checkpoint Signaling Leading to Synthetic Lethality-An Alternative Treatment Strategy for Epithelial Ovarian Cancer Cells Independent from HR Effectiveness.International journal of molecular sciences · 2020Article
Corrections and comments
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Authors and funding
9 authors at 3 institutions in 2 countries.
Funding
Abstract
We have recently shown that inhibition of HRR (homologous recombination repair) by Chk1 (checkpoint kinase 1) inhibition radiosensitizes pancreatic cancer cells and others have demonstrated that Chk1 inhibition selectively sensitizes p53 mutant tumor cells. Furthermore, PARP1 [poly (ADP-ribose) polymerase-1] inhibitors dramatically radiosensitize cells with DNA double strand break repair defects. Thus, we hypothesized that inhibition of HRR (mediated by Chk1 via AZD7762) and PARP1 [via olaparib (AZD2281)] would selectively sensitize p53 mutant pancreatic cancer cells to radiation. We also used 2 isogenic p53 cell models to assess the role of p53 status in cancer cells and intestinal epithelial cells to assess overall cancer specificity. DNA damage response and repair were assessed by flow cytometry, γH2AX, and an HRR reporter assay. We found that the combination of AZD7762 and olaparib produced significant radiosensitization in p53 mutant pancreatic cancer cells and in all of the isogenic cancer cell lines. The magnitude of radiosensitization by AZD7762 and olaparib was greater in p53 mutant cells compared with p53 wild type cells. Importantly, normal intestinal epithelial cells were not radiosensitized. The combination of AZD7762 and olaparib caused G 2 checkpoint abrogation, inhibition of HRR, and persistent DNA damage responses. These findings demonstrate that the combination of Chk1 and PARP1 inhibition selectively radiosensitizes p53 mutant pancreatic cancer cells. Furthermore, these studies suggest that inhibition of HRR by Chk1 inhibitors may be a useful strategy for selectively inducing a BRCA1/2 'deficient-like' phenotype in p53 mutant tumor cells, while sparing normal tissue.
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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.