ArticleGenes & development2017
ATR inhibition disrupts rewired homologous recombination and fork protection pathways in PARP inhibitor-resistant BRCA-deficient cancer cells.
Article in Genes & development, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 282 papers, 1 of them a synthesis that pooled it.
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
282 citing papers in PubMed, 1 synthesis or guideline pooled it, 388 citations in OpenAlex.
- The efficacy and safety of ATR inhibitors in the treatment of solid tumors: a systematic review and meta-analysis.Frontiers in oncology · 2025Pooled it
- A Phase II Study of Berzosertib in Combination with Carboplatin Compared with Docetaxel with Carboplatin in Metastatic Castration-Resistant Prostate Cancer.Cancer research communications · 2026Trial
- Ceralasertib Monotherapy in Patients with ATM-Altered Advanced Solid Tumors or Metastatic Castration-Resistant Prostate Cancer: Data from the Phase IIa PLANETTE Study.Cancer research communications · 2026Trial
- Resistance to neoadjuvant talazoparib in triple-negative breast cancer by BRN2-induced ATR/STAT3 pathways or SHLD2 subclone expansion.Proceedings of the National Academy of Sciences of the United States of America · 2026Trial
- Combination ATR and PARP Inhibitor (CAPRI): A phase 2 study of ceralasertib plus olaparib in patients with recurrent, platinum-resistant epithelial ovarian cancer.Gynecologic oncology · 2021Trial
- Ceralasertib-Mediated ATR Inhibition Combined With Olaparib in Advanced Cancers Harboring DNA Damage Response and Repair Alterations (Olaparib Combinations).JCO precision oncology · 2021Trial
- Endogenous replication stress creates a unique therapeutic window for ALC1 targeting.EMBO reports · 2026Article
- Safety and efficacy of ceralasertib, an ATR kinase inhibitor, combined with olaparib: dose escalation in advanced solid tumours and dose expansion in advanced breast cancer.British journal of cancer · 2026Article
- Distinct functions of mammalian RAD51 paralogs in genome maintenance.Biochemical Society transactions · 2026Review
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- Sensitizing Colorectal Cancer to PARP Inhibitors: Biomarkers, Mechanisms, and Combination Strategies.International journal of molecular sciences · 2026Review
- PTEN deficiency confers sensitivity to ATR inhibitor-based treatment in high-grade serous ovarian cancer.The Journal of clinical investigation · 2026Article
- Emerging Treatments in Bone Tumors: Lessons Learned from the ESMO Annual Meeting.Biomolecules · 2026Review
- PARP Inhibitor Sensitivity in Tumors Harboring Non-BRCA Homologous Recombination Gene Alterations: Current Evidence Across Ovarian, Breast, Prostate, and Pancreatic Cancers.International journal of molecular sciences · 2026Review
- Article
- Tilting the balance of life and death: navigating DNA replication stress in cancer therapy.Experimental & molecular medicine · 2026Review
- Hierarchies of resistance to DNA damage response inhibitors: from pathway restoration to replication stress tolerance.Experimental hematology & oncology · 2026Review
- USP1 inhibition promotes RAD18-dependent PCNA degradation and BRCA1 synthetic lethality.bioRxiv : the preprint server for biology · 2026Article
- ATM counteracts chromatin-bound cGAS during DNA replication.Nature cell biology · 2026Article
- Serial Spatial Transcriptomics Reveal Divergent Routes to Therapy Resistance in Metastatic Breast Cancer.Research square · 2026Article
222 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
16 authors at 4 institutions in 1 country.
Funding
Abstract
Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA1/2-deficient cells, but their efficacy in BRCA-deficient patients is limited by drug resistance. Here, we used derived cell lines and cells from patients to investigate how to overcome PARPi resistance. We found that the functions of BRCA1 in homologous recombination (HR) and replication fork protection are sequentially bypassed during the acquisition of PARPi resistance. Despite the lack of BRCA1, PARPi-resistant cells regain RAD51 loading to DNA double-stranded breaks (DSBs) and stalled replication forks, enabling two distinct mechanisms of PARPi resistance. Compared with BRCA1-proficient cells, PARPi-resistant BRCA1-deficient cells are increasingly dependent on ATR for survival. ATR inhibitors (ATRis) disrupt BRCA1-independent RAD51 loading to DSBs and stalled forks in PARPi-resistant BRCA1-deficient cells, overcoming both resistance mechanisms. In tumor cells derived from patients, ATRis also overcome the bypass of BRCA1/2 in fork protection. Thus, ATR inhibition is a unique strategy to overcome the PARPi resistance of BRCA-deficient cancers.
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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.