ArticleCancer research2016
NUDT15 Hydrolyzes 6-Thio-DeoxyGTP to Mediate the Anticancer Efficacy of 6-Thioguanine.
Article in Cancer research, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 59 papers, 2 of them syntheses that pooled it.
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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
59 citing papers in PubMed, 2 syntheses or guidelines pooled it, 127 citations in OpenAlex.
- Innovating Thiopurine Therapeutic Drug Monitoring: A Systematic Review and Meta-Analysis on DNA-Thioguanine Nucleotides (DNA-TG) as an Inclusive Biomarker in Thiopurine Therapy.Clinical pharmacokinetics · 2024Pooled it
- Impact of NUDT15 polymorphisms on thiopurines-induced myelotoxicity and thiopurines tolerance dose.Oncotarget · 2017Pooled it
- DNA-thioguanine nucleotide as a treatment marker in acute lymphoblastic leukemia patients with NUDT15 variant genotypes.PloS one · 2021Trial
- Personalized Therapy with Mercaptopurine in Acute Lymphoblastic Leukemia: Current Advances and Challenges.Current treatment options in oncology · 2026Review
- Pharmacogenomics of Thiopurine Drugs: A Bench-To-Bedside Success Story in Thailand.Clinical and translational science · 2026Review
- DNA Damage and Repair in Thyroid Physiology and Disease.Endocrine reviews · 2026Review
- NUDT5 regulates purine metabolism and thiopurine sensitivity by interacting with PPAT.Science (New York, N.Y.) · 2025Article
- Review
- Clinical Actionability of the NUDT15 *4 (p.R139H) Allele and Its Association With Hispanic Ethnicity.Clinical pharmacology and therapeutics · 2025Article
- Validation of diagnostic screening test for pharmacogenomic targets for thiopurine drugs in indian pediatric acute lymphoblastic leukemia patients.Frontiers in pharmacology · 2025Article
- The multifaceted regulatory roles of Nudix hydrolases in cancer and their therapeutic potential.Frontiers in oncology · 2025Review
- Coupling cellular drug-target engagement to downstream pharmacology with CeTEAM.Nature communications · 2024Article
- Landscape of TPMT and NUDT15 Pharmacogenetic Variation in a Cohort of Canadian Pediatric Inflammatory Bowel Disease Patients.Inflammatory bowel diseases · 2024Article
- Additive effects of TPMT and NUDT15 on thiopurine toxicity in children with acute lymphoblastic leukemia across multiethnic populations.Journal of the National Cancer Institute · 2024Article
- Article
- Targeting pan-essential pathways in cancer with cytotoxic chemotherapy: challenges and opportunities.Cancer chemotherapy and pharmacology · 2023Review
- Mammalian Nudt15 hydrolytic and binding activity on methylated guanosine mononucleotides.European biophysics journal : EBJ · 2023Article
- Comparative assessment of anti-cancer drugs against NUDT15 variants to prevent leucopenia side effect in leukemia patients.Journal, genetic engineering & biotechnology · 2023Article
- Allele-specific polymerase chain reaction can determine the diplotype of NUDT15 variants in patients with childhood acute lymphoblastic Leukemia.Scientific reports · 2023Article
- Genetic variants of genes involved in thiopurine metabolism pathway are associated with 6-mercaptopurine toxicity in pediatric acute lymphoblastic leukemia patients from Ethiopia.Frontiers in pharmacology · 2023Article
Corrections and comments
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Authors and funding
13 authors at 2 institutions in 1 country.
Funding
Abstract
Thiopurines are a standard treatment for childhood leukemia, but like all chemotherapeutics, their use is limited by inherent or acquired resistance in patients. Recently, the nucleoside diphosphate hydrolase NUDT15 has received attention on the basis of its ability to hydrolyze the thiopurine effector metabolites 6-thio-deoxyGTP (6-thio-dGTP) and 6-thio-GTP, thereby limiting the efficacy of thiopurines. In particular, increasing evidence suggests an association between the NUDT15 missense variant, R139C, and thiopurine sensitivity. In this study, we elucidated the role of NUDT15 and NUDT15 R139C in thiopurine metabolism. In vitro and cellular results argued that 6-thio-dGTP and 6-thio-GTP are favored substrates for NUDT15, a finding supported by a crystallographic determination of NUDT15 in complex with 6-thio-GMP. We found that NUDT15 R139C mutation did not affect enzymatic activity but instead negatively influenced protein stability, likely due to a loss of supportive intramolecular bonds that caused rapid proteasomal degradation in cells. Mechanistic investigations in cells indicated that NUDT15 ablation potentiated induction of the DNA damage checkpoint and cancer cell death by 6-thioguanine. Taken together, our results defined how NUDT15 limits thiopurine efficacy and how genetic ablation via the R139C missense mutation confers sensitivity to thiopurine treatment in patients. Cancer Res; 76(18); 5501-11. ©2016 AACR.
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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.