ArticleBlood advances2018
Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.
Article in Blood advances, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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
29 citing papers in PubMed, 44 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
- 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
- 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
- Combined Inhibition of ATR and Ribonucleotide Reductase Induces Synergistic Antineoplastic Activity in Osteosarcoma Cells.Cancer reports (Hoboken, N.J.) · 2026Article
- Roles of RRM2 and RRM2B in pyrimidine stress responses and differentiation of acute myeloid leukemia cells.Cell death discovery · 2026Article
- Epigenetic Biomarkers for Predicting Nucleoside Analog Drug Response and Resistance in Cancer.Biomolecules · 2026Review
- Targeting the crosstalk of metabolism reprogramming and replication stress: novel strategy to combat cancer.Medical oncology (Northwood, London, England) · 2025Review
- Checkpoint-Dependent Sensitivities to Nucleoside Analogues Uncover Specific Patterns of Genomic Instability.Current issues in molecular biology · 2025Article
- Combined inhibition of ribonucleotide reductase and WEE1 induces synergistic anticancer activity in Ewing's sarcoma cells.BMC cancer · 2025Article
- Understanding the interplay between dNTP metabolism and genome stability in cancer.Disease models & mechanisms · 2024Review
- Venetoclax Combined with Intensive Chemotherapy: A New Hope for Refractory and/or Relapsed Acute Myeloid Leukemia?Journal of clinical medicine · 2024Review
- Targeting the DNA damage response in hematological malignancies.Frontiers in oncology · 2024Review
- Synergistic anticancer activity of combined ATR and ribonucleotide reductase inhibition in Ewing's sarcoma cells.Journal of cancer research and clinical oncology · 2023Article
- Prolactin receptor signaling induces acquisition of chemoresistance and reduces clonogenicity in acute myeloid leukemia.Cancer cell international · 2023Article
- Nucleotide metabolism: a pan-cancer metabolic dependency.Nature reviews. Cancer · 2023Review
- Combined inhibition of PARP and ATR synergistically potentiates the antitumor activity of HER2-targeting antibody-drug conjugate in HER2-positive cancers.American journal of cancer research · 2023Article
- Targeting replication stress in cancer therapy.Nature reviews. Drug discovery · 2023Review
- Molecular Threat of Splicing Factor Mutations to Myeloid Malignancies and Potential Therapeutic Modulations.Biomedicines · 2022Review
- Recent Advances in Synergistic Antitumor Effects Exploited from the Inhibition of Ataxia Telangiectasia and RAD3-Related Protein Kinase (ATR).Molecules (Basel, Switzerland) · 2022Review
Corrections and comments
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Authors and funding
18 authors at 4 institutions in 1 country.
Funding
Abstract
The ataxia telangiectasia and Rad3-related (ATR) protein kinase promotes cancer cell survival by signaling stalled replication forks generated by replication stress, a common feature of many cancers including acute myeloid leukemia (AML). Here we show that the antileukemic activity of the chemotherapeutic nucleoside analogs hydroxyurea and gemcitabine was significantly potentiated by ATR inhibition via a mechanism involving ribonucleotide reductase (RNR) abrogation and inhibition of replication fork progression. When administered in combination with gemcitabine, an inhibitor of the M1 RNR subunit, the ATR inhibitor VX-970, eradicated disseminated leukemia in an orthotopic mouse model, eliciting long-term survival and effective cure. These data identify a synergistic interaction between ATR inhibition and RNR loss that will inform the deployment of small molecule inhibitors for the treatment of AML and other hematologic malignancies.
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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.