ArticleOncotarget2015
Common cancer-associated imbalances in the DNA damage response confer sensitivity to single agent ATR inhibition.
Article in Oncotarget, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 39 papers.
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Who cites it
39 citing papers in PubMed, 73 citations in OpenAlex.
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas.The Journal of clinical investigation · 2025Article
- Genotype-Directed Synthetic Cytotoxicity of ATR Inhibition with Radiotherapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2024Article
- Phase I study of peposertib and avelumab with or without palliative radiotherapy in patients with advanced solid tumors.ESMO open · 2024Article
- Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.The Journal of clinical investigation · 2024Article
- ATR inhibition using gartisertib enhances cell death and synergises with temozolomide and radiation in patient-derived glioblastoma cell lines.Oncotarget · 2024Article
- The enrichment of Fanconi anemia/homologous recombination pathway aberrations in ATM/ATR-mutated NSCLC was accompanied by unique molecular features and poor prognosis.Journal of translational medicine · 2023Article
- Therapeutic inhibition of ATR in differentiated thyroid cancer.Endocrine-related cancer · 2023Article
- Nuclear pCHK1 as a potential biomarker of increased sensitivity to ATR inhibition.The Journal of pathology · 2023Article
- Article
- Determining the Potential of DNA Damage Response (DDR) Inhibitors in Cervical Cancer Therapy.Cancers · 2022Article
- The Role of ATR Inhibitors in Ovarian Cancer: Investigating Predictive Biomarkers of Response.Cells · 2022Article
- Therapeutic targeting of ATR in alveolar rhabdomyosarcoma.Nature communications · 2022Article
- ATR Inhibitor AZD6738 (Ceralasertib) Exerts Antitumor Activity as a Monotherapy and in Combination with Chemotherapy and the PARP Inhibitor Olaparib.Cancer research · 2022Article
- RP-3500: A Novel, Potent, and Selective ATR Inhibitor that is Effective in Preclinical Models as a Monotherapy and in Combination with PARP Inhibitors.Molecular cancer therapeutics · 2022Article
- Targeting Cell Cycle Checkpoint Kinases to Overcome Intrinsic Radioresistance in Brain Tumor Cells.Cancers · 2022Review
- Sensitivity of cells to ATR and CHK1 inhibitors requires hyperactivation of CDK2 rather than endogenous replication stress or ATM dysfunction.Scientific reports · 2021Article
- Review
- Molecular matching and treatment strategies for advanced stage lung cancer at Dartmouth-Hitchcock Medical Center: A three-year review of a Molecular Tumor Board.Practical laboratory medicine · 2020Article
- Review
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
ATR is an attractive target in cancer therapy because it signals replication stress and DNA lesions for repair and to S/G2 checkpoints. Cancer-specific defects in the DNA damage response (DDR) may render cancer cells vulnerable to ATR inhibition alone. We determined the cytotoxicity of the ATR inhibitor VE-821 in isogenically matched cells with DDR imbalance. Cell cycle arrest, DNA damage accumulation and repair were determined following VE-821 exposure.Defects in homologous recombination repair (HRR: ATM, BRCA2 and XRCC3) and base excision repair (BER: XRCC1) conferred sensitivity to VE-821. Surprisingly, the loss of different components of the trimeric non-homologous end-joining (NHEJ) protein DNA-PK had opposing effects. Loss of the DNA-binding component, Ku80, caused hypersensitivity to VE-821, but loss of its partner catalytic subunit, DNA-PKcs, did not. Unexpectedly, VE-821 was particularly cytotoxic to human and hamster cells expressing high levels of DNA-PKcs. High DNA-PKcs was associated with replicative stress and activation of the DDR. VE-821 suppressed HRR, determined by RAD51 focus formation, to a greater extent in cells with high DNA-PKcs.Defects in HRR and BER and high DNA-PKcs expression, that are common in cancer, confer sensitivity to ATR inhibitor monotherapy and may be developed as predictive biomarkers for personalised medicine.
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