Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs
Audrey Lumeau, Nicolas Béry, Audrey Francès, Marion Gayral, Guillaume Labrousse, Cyril Ribeyre, Charlene Lopez, Adèle Nevot, Abdessamad El Kaoutari, Naı̈ma Hanoun, Émeline Sarot, Marion Perrier, Frédéric Pont, Juan‐Pablo Cerapio, Jean‐Jacques Fournié, Frédéric Lopez, Miguel Madrid-Mencía, Véra Pancaldi, Marie‐Jeanne Pillaire, Valérie Bergoglio, Jérôme Torrisani, Nelson Dusetti, Jean‐Sébastien Hoffmann, Louis Buscail, Malik Lutzmann, Pierre Cordelier
Abstract
Cytidine deaminase (CDA) functions in the pyrimidine salvage pathway for DNA and RNA syntheses and has been shown to protect cancer cells from deoxycytidine-based chemotherapies. In this study, we observed that CDA was overexpressed in pancreatic adenocarcinoma from patients at baseline and was essential for experimental tumor growth. Mechanistic investigations revealed that CDA localized to replication forks where it increased replication speed, improved replication fork restart efficiency, reduced endogenous replication stress, minimized DNA breaks, and regulated genetic stability during DNA replication. In cellular pancreatic cancer models, high CDA expression correlated with resistance to DNA-damaging agents. Silencing CDA in patient-derived primary cultures in vitro and in orthotopic xenografts in vivo increased replication stress and sensitized pancreatic adenocarcinoma cells to oxaliplatin. This study sheds light on the role of CDA in pancreatic adenocarcinoma, offering insights into how this tumor type modulates replication stress. These findings suggest that CDA expression could potentially predict therapeutic efficacy and that targeting CDA induces intolerable levels of replication stress in cancer cells, particularly when combined with DNA-targeted therapies. SIGNIFICANCE: Cytidine deaminase reduces replication stress and regulates DNA replication to confer resistance to DNA-damaging drugs in pancreatic cancer, unveiling a molecular vulnerability that could enhance treatment response.