ArticleMolecular oncology2019
Premature mitotic entry induced by ATR inhibition potentiates olaparib inhibition-mediated genomic instability, inflammatory signaling, and cytotoxicity in BRCA2-deficient cancer cells.
Article in Molecular oncology, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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Who cites it
52 citing papers in PubMed, 83 citations in OpenAlex.
- Tilting the balance of life and death: navigating DNA replication stress in cancer therapy.Experimental & molecular medicine · 2026Review
- Interplay Between Poly(ADP-ribosyl)ation and Specific Inner Cellular Events That Suggest Combination Strategies for Overcoming PARP Inhibitor Resistance.Pharmaceutics · 2026Review
- Targeting replication stress in neuroblastoma by exploiting the synergistic potential of second generation RRM2 and CHK1 inhibitors.Cell death & disease · 2026Article
- SLX1 silencing overcomes Olaparib resistance in metastatic castration-resistant prostate cancer by disrupting SLX4-mediated DNA repair complexes.Cancer biology & therapy · 2025Article
- The CIP2A-TOPBP1 axis facilitates mitotic DNA repair via MiDAS and MMEJ.Nature communications · 2025Article
- Safety and Tolerability of Berzosertib, an Ataxia-Telangiectasia-Related Inhibitor, and Veliparib, an Oral Poly (ADP-ribose) Polymerase Inhibitor, in Combination With Cisplatin in Patients With Refractory Solid Tumors.JCO precision oncology · 2025Article
- Elucidating DNA Damage-Dependent Immune System Activation.International journal of molecular sciences · 2025Review
- Reversing regulatory safeguards: Targeting the ATR pathway to overcome PARP inhibitor resistance.Molecular therapy. Oncology · 2025Review
- A multiparametric screen uncovers FDA-approved small molecules that potentiate the nuclear mechano-dysfunctions in ATR-defective cells.Scientific reports · 2024Article
- LAMTOR1 ablation impedes cGAS degradation caused by chemotherapy and promotes antitumor immunity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The loss of DNA polymerase epsilon accessory subunits POLE3-POLE4 leads to BRCA1-independent PARP inhibitor sensitivity.Nucleic acids research · 2024Article
- A synthetic lethal dependency on casein kinase 2 in response to replication-perturbing therapeutics in RB1-deficient cancer cells.Science advances · 2024Article
- Review
- When DNA-damage responses meet innate and adaptive immunity.Cellular and molecular life sciences : CMLS · 2024Review
- Targeting ATR in patients with cancer.Nature reviews. Clinical oncology · 2024Review
- Targeting ATR Pathway in Solid Tumors: Evidence of Improving Therapeutic Outcomes.International journal of molecular sciences · 2024Review
- The Killer's Web: Interconnection between Inflammation, Epigenetics and Nutrition in Cancer.International journal of molecular sciences · 2024Review
- BRCA2 promotes genomic integrity and therapy resistance primarily through its role in homology-directed repair.Molecular cell · 2024Article
- Enhancing immunotherapy outcomes by targeted remodeling of the tumor microenvironment via combined cGAS-STING pathway strategies.Frontiers in immunology · 2024Review
- Non-canonical role for the ataxia-telangiectasia-Rad3 pathway in STAT3 activation in human multiple myeloma cells.Cellular oncology (Dordrecht, Netherlands) · 2023Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Poly(ADP-ribose) polymerase (PARP) inhibitors are selectively cytotoxic in cancer cells with defects in homologous recombination (HR) (e.g., due to BRCA1/2 mutations). However, not all HR-deficient tumors efficiently respond to PARP inhibition and often acquire resistance. It is therefore important to uncover how PARP inhibitors induce cytotoxicity and develop combination strategies to potentiate PARP inhibitor efficacy in HR-deficient tumors. In this study, we found that forced mitotic entry upon ATR inhibition potentiates cytotoxic effects of PARP inhibition using olaparib in BRCA2-depleted and Brca2 knockout cancer cell line models. Single DNA fiber analysis showed that ATR inhibition does not exacerbate replication fork degradation. Instead, we find ATR inhibitors accelerate mitotic entry, resulting in the formation of chromatin bridges and lagging chromosomes. Furthermore, using genome-wide single-cell sequencing, we show that ATR inhibition enhances genomic instability of olaparib-treated BRCA2-depleted cells. Inhibition of CDK1 to delay mitotic entry mitigated mitotic aberrancies and genomic instability upon ATR inhibition, underscoring the role of ATR in coordinating proper cell cycle timing in situations of DNA damage. Additionally, we show that olaparib treatment leads to increased numbers of micronuclei, which is accompanied by a cGAS/STING-associated inflammatory response in BRCA2-deficient cells. ATR inhibition further increased the numbers of cGAS-positive micronuclei and the extent of cytokine production in olaparib-treated BRCA2-deficient cancer cells. Altogether, we show that ATR inhibition induces premature mitotic entry and mediates synergistic cytotoxicity with PARP inhibition in HR-deficient cancer cells, which involves enhanced genomic instability and inflammatory signaling.
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