ArticleCancer letters2023
ENT1 blockade by CNX-774 overcomes resistance to DHODH inhibition in pancreatic cancer.
Article in Cancer letters, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 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
24 citing papers in PubMed, 26 citations in OpenAlex.
- DHODH inhibition drives albumin-mediated drug resistance through TERF2IP lactylation-activated macropinosome-mitochondria contact.Nature communications · 2026Article
- KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer.Cancer research · 2026Article
- Succinate dehydrogenase loss suppresses pyrimidine biosynthesis via succinate-mediated inhibition of aspartate transcarbamylase.Nature metabolism · 2026Article
- Emerging Roles of Adenosine Metabolism in Astrocytes During Brain Injury.CNS neuroscience & therapeutics · 2026Review
- Identification of Putative Equilibrative Nucleoside Transporter Inhibitors Through Dual-Pharmacophore Virtual Screening and Validation in a Gemcitabine-Based Cell Assay.Molecules (Basel, Switzerland) · 2026Article
- Glutamine metabolism and its roles in tumor radiotherapy by regulating DNA damage repair.Frontiers in cell and developmental biology · 2026Review
- Article
- Inhibition of equilibrative nucleoside transporters 1 and 2 by proteolysis-targeting chimeras (PROTACs).The Journal of pharmacology and experimental therapeutics · 2025Article
- Tumor-stromal metabolic crosstalk in pancreatic cancer.Trends in cell biology · 2025Review
- An immunometabolic prodrug strategy overcomes DHODH inhibitor resistance in refractory melanoma.Journal of experimental & clinical cancer research : CR · 2025Article
- De novo pyrimidine biosynthesis inhibition synergizes with BCL-XNature communications · 2025Article
- Emerging pathways yielding opportunities for future treatments in pancreatic ductal adenocarcinoma.Expert opinion on therapeutic targets · 2025Review
- The perspective of targeting cancer cell metabolism: combination therapy approaches.Molecular biology reports · 2025Review
- Article
- mTORC1 regulates the pyrimidine salvage pathway by controlling UCK2 turnover via the CTLH-WDR26 E3 ligase.Cell reports · 2025Article
- Roles of nucleotide metabolism in pancreatic cancer.Frontiers in immunology · 2025Review
- Macroautophagy/autophagy promotes resistance to KRASCancer letters · 2024Article
- Site of breast cancer metastasis is independent of single nutrient levels.bioRxiv : the preprint server for biology · 2024Article
- Article
- Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.Nature cell biology · 2024Article
Corrections and comments
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Authors and funding
12 authors at 3 institutions in 1 country.
Funding
Abstract
Inhibitors of dihydroorotate dehydrogenase (DHODH), a key enzyme for de novo synthesis of pyrimidine nucleotides, have failed in clinical trials for various cancers despite robust efficacy in preclinical animal models. To probe for druggable mediators of DHODH inhibitor resistance, we performed a combination screen with a small molecule library against pancreatic cancer cell lines that are highly resistant to the DHODH inhibitor brequinar (BQ). The screen revealed that CNX-774, a preclinical Bruton tyrosine kinase (BTK) inhibitor, sensitizes resistant cell lines to BQ. Mechanistic studies showed that this effect is independent of BTK and instead results from inhibition of equilibrative nucleoside transporter 1 (ENT1) by CNX-774. We show that ENT1 mediates BQ resistance by taking up extracellular uridine, which is salvaged to generate pyrimidine nucleotides in a DHODH-independent manner. In BQ-resistant cell lines, BQ monotherapy slowed proliferation and caused modest pyrimidine nucleotide depletion, whereas combination treatment with BQ and CNX-774 led to profound cell viability loss and pyrimidine starvation. We also identify N-acetylneuraminic acid accumulation as a potential marker of the therapeutic efficacy of DHODH inhibitors. In an aggressive, immunocompetent pancreatic cancer mouse model, combined targeting of DHODH and ENT1 dramatically suppressed tumor growth and prolonged mouse survival. Overall, our study defines CNX-774 as a previously uncharacterized ENT1 inhibitor and provides strong proof of concept support for dual targeting of DHODH and ENT1 in 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.