Scientists at the University of Lausanne have identified a novel mechanism that could hinder the action of certain anti-cancer drugs
Their study, published on November 13, 2025 in the journal Nature Metabolism, highlights the key role of the NUDT5 gene in regulating nucleotide synthesis and the resistance of certain cancer cells to treatment.
Essential molecules for life... and the survival of cancer cells
Nucleotides are molecules essential to the construction of our cells’ genetic material, i.e. DNA and RNA. Nucleotide requirements are particularly high in rapidly dividing cells, such as cancer cells, and in the context of autoimmune diseases or viral infections. Many of the therapies commonly used against these pathologies are based on nucleotide analogues that mimic natural nucleotides and disrupt DNA and RNA synthesis. However, resistance frequently appears, particularly in cancer, reducing the efficacy of chemotherapies. Alexis Jourdain, Assistant Professor in the Department of Immunobiology (DIB) at the Faculty of Biology and Medicine of Biology and Medicine (FBM) at the University of Lausanne, has been investigating the mechanisms by which human cells produce nucleotides.
A key gene: NUDT5
Many of the analogues currently used clinically have to be "activated" in cells by the addition of a sugar. In a study published in the November 13, 2025 issue of Nature Metabolism, the research group demonstrated that this step is impaired in the absence of a gene called NUDT5. As a result, cancer cells expressing low levels of NUDT5 escape the cytotoxic effects of several treatments. These results were obtained in close collaboration with the FBM’s metabolomics platform.
Towards a biomarker and new therapeutic strategies
This work positions NUDT5 as a promising biomarker for predicting therapeutic resistance in cancer, autoimmune diseases and viral infections, which will help guide practitioners in their choice of therapies. But that’s not all! Acting directly on this key element could make resistant cells sensitive to nucleotide analogues again. "By understanding how cells regulate nucleotide activation, we are opening up new prospects for improving the efficacy of existing treatments", concludes Abigail Alexandre-Strefeler , PhD student at the FBM in the Jourdain Lab and first author of the article.
Reference
Strefeler, A., Baker, Z.N., Chollet, S. et al. Uridine-sensitized screening identifies demethoxy-coenzyme Q and NUDT5 as regulators of nucleotide synthesis. Nat Metab (2025). https://doi.org/10.1038/s42255-025-01419-2
