A cytidine deaminase biodegrader sensitises multiple cancer types to deoxycytidine analogue-based chemotherapies
Abstract
Deoxycytidine (dC) analogues are widely used to treat solid tumours and blood cancers. However, their clinical efficacy is often limited by resistance mediated by cytidine deaminase (CDA), which converts these drugs into inactive metabolites. Existing CDA inhibitors have limited efficacy and off-target effects, highlighting the need for alternative approaches. Here, we show the development of a CDA biodegrader, an intracellular anti-CDA VHH fused to the SPOP E3 ubiquitin ligase, enabling specific CDA degradation. It effectively depletes CDA in pancreatic, lung, and acute myeloid leukaemia cancer cell lines, increasing sensitivity to dC analogues in vitro. Combined with gemcitabine, the CDA biodegrader inhibits pancreatic and lung tumour growth in vivo. Importantly, mRNA encoding the biodegrader delivered using virus-like particles achieves efficient sensitisation to gemcitabine in vitro and in vivo. This proof-of-concept study establishes targeted CDA degradation as a feasible strategy to enhance the therapeutic efficacy of dC analogues.
Related
BibTeX
@article{sorbara2026cytidine,
title = {{A cytidine deaminase biodegrader sensitises multiple cancer types to deoxycytidine analogue-based chemotherapies}},
author = {Marie Sorbara and Margot Cristol and Charlène Lopez and Ben Allal and Manon Gervais and Anaïs Faihy and Margaux Vienne and Naïma Hanoun and Constance Manso and Alexandre Stella and Laetitia Ligat and Odile Burlet-Schiltz and Etienne Chatelut and Laura Poillet and Carine Joffre and Fabienne Thomas and Pierre Cordelier and Nicolas Bery},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-78315-0},
url = {https://www.nature.com/articles/s41467-026-78315-0},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A cytidine deaminase biodegrader sensitises multiple cancer types to deoxycytidine analogue-based chemotherapies
AU - Marie Sorbara
AU - Margot Cristol
AU - Charlène Lopez
AU - Ben Allal
AU - Manon Gervais
AU - Anaïs Faihy
AU - Margaux Vienne
AU - Naïma Hanoun
AU - Constance Manso
AU - Alexandre Stella
AU - Laetitia Ligat
AU - Odile Burlet-Schiltz
AU - Etienne Chatelut
AU - Laura Poillet
AU - Carine Joffre
AU - Fabienne Thomas
AU - Pierre Cordelier
AU - Nicolas Bery
PY - 2026
DA - 2026/10/07
JO - Nature Communications
DO - 10.1038/s41467-026-78315-0
UR - https://www.nature.com/articles/s41467-026-78315-0
AB - Deoxycytidine (dC) analogues are widely used to treat solid tumours and blood cancers. However, their clinical efficacy is often limited by resistance mediated by cytidine deaminase (CDA), which converts these drugs into inactive metabolites. Existing CDA inhibitors have limited efficacy and off-target effects, highlighting the need for alternative approaches. Here, we show the development of a CDA biodegrader, an intracellular anti-CDA VHH fused to the SPOP E3 ubiquitin ligase, enabling specific CDA degradation. It effectively depletes CDA in pancreatic, lung, and acute myeloid leukaemia cancer cell lines, increasing sensitivity to dC analogues in vitro. Combined with gemcitabine, the CDA biodegrader inhibits pancreatic and lung tumour growth in vivo. Importantly, mRNA encoding the biodegrader delivered using virus-like particles achieves efficient sensitisation to gemcitabine in vitro and in vivo. This proof-of-concept study establishes targeted CDA degradation as a feasible strategy to enhance the therapeutic efficacy of dC analogues.
SN - 2041-1723
ER -