ArticleOncology reports2017
Inhibition of ATR potentiates the cytotoxic effect of gemcitabine on pancreatic cancer cells through enhancement of DNA damage and abrogation of ribonucleotide reductase induction by gemcitabine.
Article in Oncology reports, 2017. 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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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.
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Who cites it
20 citing papers in PubMed, 30 citations in OpenAlex.
- Randomized Phase II Study of Gemcitabine With or Without ATR Inhibitor Berzosertib in Platinum-Resistant Ovarian Cancer: Final Overall Survival and Biomarker Analyses.JCO precision oncology · 2024Trial
- Effect of Cisplatin and Gemcitabine With or Without Berzosertib in Patients With Advanced Urothelial Carcinoma: A Phase 2 Randomized Clinical Trial.JAMA oncology · 2021Trial
- A Replication stress biomarker is associated with response to gemcitabine versus combined gemcitabine and ATR inhibitor therapy in ovarian cancer.Nature communications · 2021Trial
- Berzosertib plus gemcitabine versus gemcitabine alone in platinum-resistant high-grade serous ovarian cancer: a multicentre, open-label, randomised, phase 2 trial.The Lancet. Oncology · 2020Trial
- Camonsertib, an ATRi, in Combination with Low-Dose Gemcitabine in Solid Tumors with DNA Damage Response Aberrations: Preclinical and Phase Ib Results.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026Article
- Elimusertib enhances cytotoxic effects of conventional chemotherapy and sensitizes to radiation in preclinical Ewing sarcoma models.Scientific reports · 2026Article
- Targeting ATR-CHK1 and ATM-CHK2 Axes in Pancreatic Cancer-A Comprehensive Review of Literature.International journal of molecular sciences · 2026Review
- Key Proteins of Replication Stress Response and Cell Cycle Control as Cancer Therapy Targets.International journal of molecular sciences · 2024Review
- Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells.Journal of cancer research and clinical oncology · 2023Article
- ATR Inhibition in Advanced Urothelial Carcinoma.Clinical genitourinary cancer · 2023Review
- Targeting replication stress in cancer therapy.Nature reviews. Drug discovery · 2023Review
- DNA damage response revisited: the p53 family and its regulators provide endless cancer therapy opportunities.Experimental & molecular medicine · 2022Review
- Effects of CXCL12 isoforms in a pancreatic pre-tumour cellular model: Microarray analysis.World journal of gastroenterology · 2021Article
- Doxycycline potentiates the anti-proliferation effects of gemcitabine in pancreatic cancer cells.American journal of cancer research · 2021Article
- ATM Inhibitor Suppresses Gemcitabine-Resistant BTC Growth in a Polymerase θ Deficiency-Dependent Manner.Biomolecules · 2020Article
- Fisetin inhibits proliferation of pancreatic adenocarcinoma by inducing DNA damage via RFXAP/KDM4A-dependent histone H3K36 demethylation.Cell death & disease · 2020Article
- Glutamine deprivation counteracts hypoxia-induced chemoresistance.Neoplasia (New York, N.Y.) · 2020Article
- Targeting ATR in cancer.Nature reviews. Cancer · 2018Review
- The ATR Inhibitor AZD6738 Synergizes with GemcitabineMolecular cancer therapeutics · 2018Article
- Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.Blood advances · 2018Article
Corrections and comments
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Authors and funding
8 authors at 3 institutions in 2 countries.
Funding
Abstract
Pancreatic cancer is a highly malignant disease with a dismal prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line treatment for patients with advanced disease, although its efficacy is very limited, mainly due to drug resistance. Ataxia telangiectasia and Rad3-related (ATR) plays a critical role in the DNA damage response (DDR) which has been implicated in GEM resistance. Thus, targeting ATR represents a promising approach to enhance GEM antitumor activity. In the present study, we tested the antitumor activity of AZ20, a novel ATR-selective inhibitor, alone or combined with GEM in 5 pancreatic cancer cell lines. AZ20 treatment of the pancreatic cancer cell lines resulted in growth inhibition, with IC50 values ranging from 0.84 to 2.4 µM, but limited cell death. As expected, treatment of pancreatic cancer cell lines with AZ20 caused decreased phosphorylation of CHK1 (S-345). However, this was accompanied by DNA damage and S and G2/M cell cycle arrest, independent of TP53 gene mutational status. Importantly, combination of AZ20 with GEM resulted in synergistic inhibition of cell growth and cooperative induction of cell death in the pancreatic cancer cell lines. AZ20 significantly increased GEM-induced DNA damage and almost completely abrogated GEM-induced expression of the M2 subunit of ribonucleotide reductase. These findings suggest that inhibition of ATR is a promising strategy to enhance the antitumor activity of GEM for treating pancreatic cancer.
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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.