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Figure S1 from Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs

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posted on 2024-04-01, 07:24 authored by Audrey Lumeau, Nicolas Bery, Audrey Francès, Marion Gayral, Guillaume Labrousse, Cyril Ribeyre, Charlene Lopez, Adele Nevot, Abdessamad El Kaoutari, Naima Hanoun, Emeline Sarot, Marion Perrier, Frederic Pont, Juan-Pablo Cerapio, Jean-Jacques Fournié, Frederic Lopez, Miguel Madrid-Mencia, Vera Pancaldi, Marie-Jeanne Pillaire, Valerie Bergoglio, Jerome Torrisani, Nelson Dusetti, Jean-Sebastien Hoffmann, Louis Buscail, Malik Lutzmann, Pierre Cordelier

Figure S1

Funding

Fondation Toulouse Cancer Santé (Toulouse Cancer Health Foundation)

Region Occitanie

Institut National de la Santé et de la Recherche Médicale (Inserm)

Universite Paul Sabatier Toulouse III

Fondation de France (Foundation of France)

Ligue Contre le Cancer (French League Against Cancer)

Inserm Transfert (Inserm Transfert SA)

History

ARTICLE 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. 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.