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Cytidine Deaminase Resolves Replicative Stress and Protects Pancreatic Cancer from DNA-Targeting Drugs.
Lumeau, Audrey; Bery, Nicolas; Francès, Audrey; Gayral, Marion; Labrousse, Guillaume; Ribeyre, Cyril; Lopez, Charlene; Nevot, Adele; El Kaoutari, Abdessamad; Hanoun, Naima; Sarot, Emeline; Perrier, Marion; Pont, Frederic; Cerapio, Juan-Pablo; Fournié, Jean-Jacques; Lopez, Frederic; Madrid-Mencia, Miguel; Pancaldi, Vera; Pillaire, Marie-Jeanne; Bergoglio, Valerie; Torrisani, Jerome; Dusetti, Nelson; Hoffmann, Jean-Sebastien; Buscail, Louis; Lutzmann, Malik; Cordelier, Pierre.
Afiliación
  • Lumeau A; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Bery N; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Francès A; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Gayral M; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Labrousse G; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Ribeyre C; Institut de Génétique Humaine, CNRS, Université de Montpellier, Montpellier, France.
  • Lopez C; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Nevot A; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • El Kaoutari A; Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Université Aix-Marseille, Marseille, France.
  • Hanoun N; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Sarot E; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Perrier M; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Pont F; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Cerapio JP; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Fournié JJ; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Lopez F; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Madrid-Mencia M; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Pancaldi V; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Pillaire MJ; Barcelona Supercomputing Center, Barcelona, Spain.
  • Bergoglio V; Institut de Pharmacologie et de Biologie Structurale, IPBS, Toulouse, France.
  • Torrisani J; Centre de Biologie Intégrée, CBI, Toulouse, France.
  • Dusetti N; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Hoffmann JS; Centre de Recherche en Cancérologie de Marseille, CRCM, Inserm, CNRS, Institut Paoli-Calmettes, Université Aix-Marseille, Marseille, France.
  • Buscail L; Laboratoire d'Excellence Toulouse Cancer (TOUCAN), Laboratoire de pathologie, Institut Universitaire du Cancer-Toulouse, Toulouse, France.
  • Lutzmann M; Centre de Recherches en Cancérologie de Toulouse, CRCT, Université de Toulouse, Inserm, CNRS, Toulouse, France.
  • Cordelier P; Service de gastroentérologie et d'hépatologie, CHU Rangueil, Université de Toulouse, Toulouse, France.
Cancer Res ; 84(7): 1013-1028, 2024 Apr 01.
Article en En | MEDLINE | ID: mdl-38294491
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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Adenocarcinoma / Inhibidores de la Síntesis del Ácido Nucleico / Citidina Desaminasa Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Adenocarcinoma / Inhibidores de la Síntesis del Ácido Nucleico / Citidina Desaminasa Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cancer Res Año: 2024 Tipo del documento: Article País de afiliación: Francia Pais de publicación: Estados Unidos