ArticleThe Journal of experimental medicine2014
Co-targeting of convergent nucleotide biosynthetic pathways for leukemia eradication.
Article in The Journal of experimental medicine, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 43 citations in OpenAlex.
- Deoxycytidine kinase inhibition: Rewiring tumor nucleotide metabolism for therapeutic gain.Nucleosides, nucleotides & nucleic acids · 2026Review
- Metabolomic Profiling and Bioanalysis of Chronic Myeloid Leukemia: Identifying Biomarkers for Treatment Response and Disease Monitoring.Metabolites · 2025Article
- Landscape of targets within nucleoside metabolism for the modification of immune responses.Frontiers in oncology · 2025Review
- N6-methyladenosine RNA methylation, a new hallmark of metabolic reprogramming in the immune microenvironment.Frontiers in immunology · 2024Review
- Establishment and verification of a prognostic risk score model based on immune genes for hepatocellular carcinoma in an Asian population.Translational cancer research · 2023Article
- From a drug repositioning to a structure-based drug design approach to tackle acute lymphoblastic leukemia.Nature communications · 2023Article
- Nucleotide metabolism: a pan-cancer metabolic dependency.Nature reviews. Cancer · 2023Review
- Dithiocarbazate ligands and their Ni(II) complexes with potential biological activity: Structural, antitumor and molecular docking study.Frontiers in molecular biosciences · 2023Article
- Targeting deoxycytidine kinase improves symptoms in mouse models of multiple sclerosis.Immunology · 2023Article
- Article
- Review
- STING-driven interferon signaling triggers metabolic alterations in pancreas cancer cells visualized by [Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Metabolomic therapy response prediction in pretherapeutic tissue biopsies for trastuzumab in patients with HER2-positive advanced gastric cancer.Clinical and translational medicine · 2021Article
- Decitabine- and 5-azacytidine resistance emerges from adaptive responses of the pyrimidine metabolism network.Leukemia · 2021Article
- Isoquinoline thiosemicarbazone displays potent anticancer activity withRSC medicinal chemistry · 2020Article
- Metabolic Modifier Screen Reveals Secondary Targets of Protein Kinase Inhibitors within Nucleotide Metabolism.Cell chemical biology · 2020Article
- Development and preclinical pharmacology of a novel dCK inhibitor, DI-87.Biochemical pharmacology · 2020Article
- Review
- Lysosome inhibition sensitizes pancreatic cancer to replication stress by aspartate depletion.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Inhibition of ATR acutely sensitizes acute myeloid leukemia cells to nucleoside analogs that target ribonucleotide reductase.Blood advances · 2018Article
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Authors and funding
27 authors at 4 institutions in 1 country.
Funding
Abstract
Pharmacological targeting of metabolic processes in cancer must overcome redundancy in biosynthetic pathways. Deoxycytidine (dC) triphosphate (dCTP) can be produced both by the de novo pathway (DNP) and by the nucleoside salvage pathway (NSP). However, the role of the NSP in dCTP production and DNA synthesis in cancer cells is currently not well understood. We show that acute lymphoblastic leukemia (ALL) cells avoid lethal replication stress after thymidine (dT)-induced inhibition of DNP dCTP synthesis by switching to NSP-mediated dCTP production. The metabolic switch in dCTP production triggered by DNP inhibition is accompanied by NSP up-regulation and can be prevented using DI-39, a new high-affinity small-molecule inhibitor of the NSP rate-limiting enzyme dC kinase (dCK). Positron emission tomography (PET) imaging was useful for following both the duration and degree of dCK inhibition by DI-39 treatment in vivo, thus providing a companion pharmacodynamic biomarker. Pharmacological co-targeting of the DNP with dT and the NSP with DI-39 was efficacious against ALL models in mice, without detectable host toxicity. These findings advance our understanding of nucleotide metabolism in leukemic cells, and identify dCTP biosynthesis as a potential new therapeutic target for metabolic interventions in ALL and possibly other hematological malignancies.
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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.