ArticleBritish journal of cancer2024
ATR, CHK1 and WEE1 inhibitors cause homologous recombination repair deficiency to induce synthetic lethality with PARP inhibitors.
Article in British journal of cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Antitumor activity and structure-activity relationship of poly (ADP-ribose) polymerase (PARP)-based dual inhibitors.Journal of enzyme inhibition and medicinal chemistry · 2026Review
- Ataxia-Telangiectasia, DNA Repair Deficits, Immune Dysfunction, and Cancer: A Review of Mechanisms, Clinical Presentations, and Emerging Therapies.Clinical reviews in allergy & immunology · 2026Review
- Review
- ERCC6 at the Transcription-Replication Interface: Integration of Transcription-Coupled Repair with Replication Stress Responses.International journal of molecular sciences · 2026Review
- Emerging Therapeutic Strategies in Small-Cell Lung Cancer: From Adaptive Resistance to Precision Therapy.Pharmaceuticals (Basel, Switzerland) · 2026Review
- RMI2 knockdown suppresses ovarian cancer cell growth by impairing DNA damage repair via the ATR/CHK1 signaling pathway.In vitro cellular & developmental biology. Animal · 2026Article
- Preoperative PARP Inhibitors in Ovarian Cancer Trials: Connecting Molecular Oncology and Cytoreductive Surgery.Cancers · 2026Review
- Overcoming Resistance in Triple-Negative Breast Cancer: A Translational Perspective on Next-Generation DNA Damage Response Inhibitors and Synthetic Lethality.Molecules (Basel, Switzerland) · 2026Review
- Progress on the mechanism of Piezo1 in mechanical ventilation-induced lung injury.Journal of thoracic disease · 2026Review
- Sequencing PARP inhibitors in breast cancer: lessons learned and emerging insights.NPJ breast cancer · 2026Review
- Targeting VEGF, PARP, and FRα Pathways in Ovarian Cancer: Clinical Advances with Bevacizumab, Rucaparib, and Mirvetuximab Soravtansine.Journal of clinical medicine · 2026Review
- Exploiting synthetic lethality in epithelial ovarian cancer: multi-dimensional approaches beyond DNA damage repair.Molecular cancer · 2026Review
- Breast Cancer Brain Metastases: Current Understanding and Future Directions.Current oncology reports · 2026Review
- PARylation-centric crosstalk: orchestrating immune evasion and multidrug resistance in ovarian cancer.Frontiers in immunology · 2026Review
- Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance.Clinical and translational medicine · 2026Review
- Molecular mechanisms of KMT2C alterations in gastrointestinal cancers: enhancer network destabilization, lineage plasticity, and clinical translation.Frontiers in immunology · 2026Review
- Dual inhibition of ATR and PARP reverses acquired PARP inhibitor resistance in triple negative breast cancer.Discover oncology · 2025Article
- Cancer Vulnerabilities Through Targeting the ATR/Chk1 and ATM/Chk2 Axes in the Context of DNA Damage.Cells · 2025Review
- Reversing regulatory safeguards: Targeting the ATR pathway to overcome PARP inhibitor resistance.Molecular therapy. Oncology · 2025Review
- The Potential for Targeting GCancers · 2024Review
Corrections and comments
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Authors and funding
4 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
purposePARP inhibitors (PARPi) are effective in homologous recombination repair (HRR) defective (HRD) cancers. To (re)sensitise HRR proficient (HRP) tumours to PARPi combinations with other drugs are being explored. Our aim was to determine the mechanism underpinning the sensitisation to PARPi by inhibitors of cell cycle checkpoint kinases ATR, CHK1 and WEE1. EXPERIMENTAL
designA panel of HRD and HRP cells (including matched BRCA1 or 2 mutant and corrected pairs) and ovarian cancer ascites cells were used. Rucaparib (PARPi) induced replication stress (RS) and HRR (immunofluorescence microscopy for γH2AX and RAD51 foci, respectively), cell cycle changes (flow cytometry), activation of ATR, CHK1 and WEE1 (Western Blot for pCHK1S345, pCHK1S296 and pCDK1Y15, respectively) and cytotoxicity (colony formation assay) was determined, followed by investigations of the impact on all of these parameters by inhibitors of ATR (VE-821, 1 µM), CHK1 (PF-477736, 50 nM) and WEE1 (MK-1775, 100 nM).
resultsRucaparib induced RS (3 to10-fold), S-phase accumulation (2-fold) and ATR, CHK1 and WEE1 activation (up to 3-fold), and VE-821, PF-477736 and MK-1775 inhibited their targets and abrogated these rucaparib-induced cell cycle changes in HRP and HRD cells. Rucaparib activated HRR in HRP cells only and was (60-1,000x) more cytotoxic to HRD cells. VE-821, PF-477736 and MK-1775 blocked HRR and sensitised HRP but not HRD cells and primary ovarian ascites to rucaparib.
conclusionsOur data indicate that, rather than acting via abrogation of cell cycle checkpoints, ATR, CHK1 and WEE1 inhibitors cause an HRD phenotype and hence "induced synthetic lethality" with PARPi.
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