ArticleScientific reports2023
Targeted inhibition of the ATR/CHK1 pathway overcomes resistance to olaparib and dysregulates DNA damage response protein expression in BRCA2
Article in Scientific reports, 2023. 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, 19 citations in OpenAlex.
- STN1 upregulation promotes PARPi resistance in BRCA2-deficient cancer cells via replication fork protection and suppression of ssDNA gap formation.NAR cancer · 2026Article
- STN1 upregulation promotes PARPi resistance in BRCA2-deficient cancer cells via replication fork protection and suppression of ssDNA gap formation.bioRxiv : the preprint server for biology · 2026Article
- Progress on the mechanism of Piezo1 in mechanical ventilation-induced lung injury.Journal of thoracic disease · 2026Review
- Review
- Targeting KIF18B overcomes oxaliplatin resistance in esophageal squamous cell carcinoma via suppression of the ATR/CHK1 axis.Molecular genetics and genomics : MGG · 2026Article
- Precision oncology in gynecologic cancers: molecular taxonomy, biomarker-guided therapeutics, and the challenge of therapeutic resistance.Frontiers in oncology · 2026Review
- Prostate-Specific Membrane Antigen (PSMA)-Directed Dendrimer-Camptothecin Conjugate for Targeted Treatment of Prostate Cancer.ACS applied nano materials · 2025Article
- Navigating PARP Inhibitor Resistance in Ovarian Cancer: Bridging Mechanistic Insights To Clinical Translation.Current treatment options in oncology · 2025Review
- Review
- Therapeutic resistance and combination therapy for cancer: recent developments and future directions.Scientific reports · 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
- Precision Medicine in High-Grade Serous Ovarian Cancer: Targeted Therapies and the Challenge of Chemoresistance.International journal of molecular sciences · 2025Review
- Olaparib promotes FABP4 expression and reduces antitumor effect in ovarian cancer cells with aOncology letters · 2025Article
- Controversies and clinical unknowns in the use of PARP inhibitors in ovarian cancer.Therapeutic advances in medical oncology · 2025Review
- Targeting synthetic lethality: an effective therapeutic approach in ovarian and endometrial cancers.Therapeutic advances in medical oncology · 2025Review
- A multiparametric screen uncovers FDA-approved small molecules that potentiate the nuclear mechano-dysfunctions in ATR-defective cells.Scientific reports · 2024Article
- Uncovering miRNA-mRNA Regulatory Networks Related to Olaparib Resistance and Resensitization ofCells · 2024Article
- Poly (ADP-ribose) polymerase inhibitor therapy and mechanisms of resistance in epithelial ovarian cancer.Frontiers in oncology · 2024Review
- Telomere-related DNA damage response pathways in cancer therapy: prospective targets.Frontiers in pharmacology · 2024Review
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Olaparib is a PARP inhibitor (PARPi) approved for targeted treatment of ovarian cancer (OC). However, its efficacy is impeded by the inevitable occurrence of resistance. Here, we investigated whether the cytotoxic activity of olaparib could be synergistically enhanced in olaparib-resistant OC cells with BRCA2 reversion mutation by the addition of inhibitors of the ATR/CHK1 pathway. Moreover, we provide insights into alterations in the DNA damage response (DDR) pathway induced by combination treatments. Antitumor activity of olaparib alone or combined with an ATR inhibitor (ATRi, ceralasertib) or CHK1 inhibitor (CHK1i, MK-8776) was evaluated in OC cell lines sensitive (PEO1, PEO4) and resistant (PEO1-OR) to olaparib. Antibody microarrays were used to explore changes in expression of 27 DDR-related proteins. Olaparib in combination with ATR/CHK1 inhibitors synergistically induced a decrease in viability and clonogenic survival and an increase in apoptosis mediated by caspase-3/7 in all OC cells. Combination treatments induced cumulative alterations in expression of DDR-related proteins mediating distinct DNA repair pathways and cell cycle control. In the presence of ATRi and CHK1i, olaparib-induced upregulation of proteins determining cell fate after DNA damage (PARP1, CHK1, c-Abl, Ku70, Ku80, MDM2, and p21) was abrogated in PEO1-OR cells. Overall, the addition of ATRi or CHK1i to olaparib effectively overcomes resistance to PARPi exerting anti-proliferative effect in BRCA2
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