ArticleCancer research2022
Resistance to ATR Inhibitors Is Mediated by Loss of the Nonsense-Mediated Decay Factor UPF2.
Article in Cancer research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
What it found
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The trial behind it
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Who cites it
18 citing papers in PubMed, 27 citations in OpenAlex.
- Synthetic lethality in cancer: mechanisms, therapeutic exploitation and clinical translation.Signal transduction and targeted therapy · 2026Review
- Targeting epigenetic regulators induces transcription-replication conflicts to overcome ATR inhibitor resistance.Nucleic acids research · 2026Article
- FET Fusion Oncoproteins Disrupt Physiologic DNA Repair and Create a Targetable Opportunity for ATR Inhibitor Therapy.Cancer research · 2026Article
- X-ray preactivated reversible persistent luminescence enables photodynamic immunotherapy of deep tumors.Nature communications · 2026Article
- Transcriptional Profiling Reveals Lineage-Specific Characteristics in ATR/CHK1 Inhibitor-Resistant Endometrial Cancer.Biomolecules · 2026Article
- Replication Stress in Cancer: Mechanistic Insights and Therapeutic Opportunities for Radiosensitization.Current issues in molecular biology · 2026Review
- R‑loops in hepatocellular carcinoma: Bridging genomic instability and therapeutic opportunity (Review).Molecular medicine reports · 2026Review
- Targeting ATR offers multifaceted treatment strategies involving RAD51-mediated compensatory DNA repair in bladder cancer.Journal of experimental & clinical cancer research : CR · 2025Article
- ATR-CHK1 Axis Inhibitors in Gastric Cancer Treatment.International journal of molecular sciences · 2025Review
- Multidrug Resistance: Are We Still Afraid of the Big Bad Wolf.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Insights From Nonsense-Mediated mRNA Decay for Prognosis in Homologous Recombination-Deficient Ovarian Cancer.Cancer science · 2025Article
- KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.Nature communications · 2025Article
- DNA damage response inhibitors in cancer therapy: lessons from the past, current status and future implications.Nature reviews. Drug discovery · 2025Review
- Transcription and DNA replication collisions lead to large tandem duplications and expose targetable therapeutic vulnerabilities in cancer.Nature cancer · 2024Article
- PARP inhibition leads to synthetic lethality with key splicing-factor mutations in myelodysplastic syndromes.British journal of cancer · 2024Article
- Large tandem duplications in cancer result from transcription and DNA replication collisions.medRxiv : the preprint server for health sciences · 2024Article
- Multidrug resistance transporters P-gp and BCRP limit the efficacy of ATR inhibitor ceralasertib in cancer cells.Frontiers in pharmacology · 2024Article
- Emerging strategies for cancer therapy by ATR inhibitors.Cancer science · 2023Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
Over one million cases of gastric cancer are diagnosed each year globally, and the metastatic disease continues to have a poor prognosis. A significant proportion of gastric tumors have defects in the DNA damage response pathway, creating therapeutic opportunities through synthetic lethal approaches. Several small-molecule inhibitors of ATR, a key regulator of the DNA damage response, are now in clinical development as targeted agents for gastric cancer. Here, we performed a large-scale CRISPR interference screen to discover genetic determinants of response and resistance to ATR inhibitors (ATRi) in gastric cancer cells. Among the top hits identified as mediators of ATRi response were UPF2 and other components of the nonsense-mediated decay (NMD) pathway. Loss of UPF2 caused ATRi resistance across multiple gastric cancer cell lines. Global proteomic, phosphoproteomic, and transcriptional profiling experiments revealed that cell-cycle progression and DNA damage responses were altered in UPF2-mutant cells. Further studies demonstrated that UPF2-depleted cells failed to accumulate in G1 following treatment with ATRi. UPF2 loss also reduced transcription-replication collisions, which has previously been associated with ATRi response, thereby suggesting a possible mechanism of resistance. Our results uncover a novel role for NMD factors in modulating response to ATRi in gastric cancer, highlighting a previously unknown mechanism of resistance that may inform the clinical use of these drugs. SIGNIFICANCE: Loss of NMD proteins promotes resistance to ATR inhibitors in gastric cancer cells, which may provide a combination of therapeutic targets and biomarkers to improve the clinical utility of these drugs.
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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.