ArticleBritish journal of cancer2020
Complete loss of ATM function augments replication catastrophe induced by ATR inhibition and gemcitabine in pancreatic cancer models.
Article in British journal of cancer, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers.
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Who cites it
48 citing papers in PubMed, 58 citations in OpenAlex.
- Targeting epigenetic regulators induces transcription-replication conflicts to overcome ATR inhibitor resistance.Nucleic acids research · 2026Article
- Low-Rank Variational Correction Estimation for Multi-Source Heterogeneous Quantile Linear Regression Models.Statistics in medicine · 2026Article
- Common DNA Damage Response Factors Required for Cellular Resistance to Inhibitors for the Ataxia Telangiectasia and Rad3-Related Checkpoint Kinase in Hematopoietic Cells.Biomolecules · 2026Article
- ATR kinase inhibitors induce mitochondrial fission in CD8bioRxiv : the preprint server for biology · 2026Article
- A phosphorylation switch at MRE11 links ATM-ATR and calcium signaling to safeguard stalled replication fork stability.Research square · 2026Article
- Berzosertib enhances the sensitivity of pediatric diffuse midline glioma H3K27-altered cells to radiotherapy.Cell death & disease · 2026Article
- Microenvironmental acidosis drives PARP- and ATM inhibitor resistance in p53 deficient pancreatic cancer.iScience · 2026Article
- Targeting ATR-CHK1 and ATM-CHK2 Axes in Pancreatic Cancer-A Comprehensive Review of Literature.International journal of molecular sciences · 2026Review
- Radiogenomics and the DNA damage response: opportunities for biomarker-guided radiosensitization in pancreatic cancer.Frontiers in oncology · 2026Review
- Replication-associated base excision repair/single-strand break repair regulates PARG inhibitor response via the PRMT1/PRMT5/ATR axis.NAR cancer · 2025Article
- Targeting DNA Damage Response and Immune Crosstalk in Cancer: Mechanistic Insights and Therapeutic Opportunities.International journal of molecular sciences · 2025Review
- Targeting DNA Damage Repair Pathways Beyond PARP Inhibition.Targeted oncology · 2025Review
- ATR inhibition potentiates FOLFIRINOX cytotoxic effect in models of pancreatic ductal adenocarcinoma by remodelling the tumour microenvironment.British journal of cancer · 2025Article
- Pancreatic cancer: failures and hopes-a review of new promising treatment approaches.Exploration of targeted anti-tumor therapy · 2025Review
- Synthetic lethal strategies for the development of cancer therapeutics.Nature reviews. Clinical oncology · 2025Review
- Combined MEK1/2 and ATR inhibition promotes myeloma cell death through a STAT3-dependent mechanism in vitro and in vivo.British journal of haematology · 2024Article
- Targeting ATR in patients with cancer.Nature reviews. Clinical oncology · 2024Review
- Triple-Negative Breast Cancer and Emerging Therapeutic Strategies: ATR and CHK1/2 as Promising Targets.Cancers · 2024Review
- The Future of Targeted Therapy for Leiomyosarcoma.Cancers · 2024Review
- Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets.International journal of molecular sciences · 2024Review
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Authors and funding
9 authors at 2 institutions in 1 country.
Funding
Abstract
backgroundPersonalised medicine strategies may improve outcomes in pancreatic ductal adenocarcinoma (PDAC), but validation of predictive biomarkers is required. Having developed a clinical trial to assess the ATR inhibitor, AZD6738, in combination with gemcitabine (ATRi/gem), we investigated ATM loss as a predictive biomarker of response to ATRi/gem in PDAC.
methodsThrough kinase inhibition, siRNA depletion and CRISPR knockout of ATM, we assessed how ATM targeting affected the sensitivity of PDAC cells to ATRi/gem. Using flow cytometry, immunofluorescence and immunoblotting, we investigated how ATRi/gem synergise in ATM-proficient and ATM-deficient cells, before assessing the impact of ATM loss on ATRi/gem sensitivity in vivo.
resultsComplete loss of ATM function (through pharmacological inhibition or CRISPR knockout), but not siRNA depletion, sensitised to ATRi/gem. In ATM-deficient cells, ATRi/gem-induced replication catastrophe was augmented, while phospho-Chk2-T68 and phospho-KAP1-S824 persisted via DNA-PK activity. ATRi/gem caused growth delay in ATM-WT xenografts in NSG mice and induced regression in ATM-KO xenografts.
conclusionsATM loss augments replication catastrophe-mediated cell death induced by ATRi/gem and may predict clinical responsiveness to this combination. ATM status should be carefully assessed in tumours from patients with PDAC, since distinction between ATM-low and ATM-null could be critical in maximising the success of clinical trials using ATM expression as a predictive biomarker.
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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.