Résumé
Cytidine deaminase (CDA) converts cytidine and deoxycytidine into uridine and deoxyuridine within the pyrimidine salvage pathway for DNA and RNA synthesis. In this regard, loss of CDA provokes genomic instability in Bloom Syndrome, and CDA overexpression is associated with tumor resistance to chemotherapy with pyrimidine analogs. However, the precise role of CDA per se in cancer has been totally underexplored so far. Patient cohort analysis demonstrate that CDA is overexpressed in PDAC, a disease with no cure with increasing incidence, and associated with a worse prognosis in patient. Functional studies demonstrate that CDA is essential to PDAC cell proliferation and tumor growth. We found that CDA expression is associated with gene set enrichment in DNA replication signature, in both PDAC tumors and experimental models. Using enforced expression, genetic or pharmacologic targeting, we demonstrate that CDA promotes DNA replication, localizes to the replication fork and increases replication fork fitness. These effects are strictly dependent on CDA deaminase activity. Hence, we found that CDA controls replication stress as CDA expression is inversely correlated with the level of DNA breaks during S-phase, and that CDA targeting is associated with gene set enrichment in replication stress signature and CHK1 protein activation. Next, we demonstrate that CDA preserves genomic stability of PDAC cells, as CDA expression is inversely correlated with micronuclei formation and DNA damage transfer to daughter cells. We next explored PDAC cell lines from the Cancer Cell Lines Encyclopedia and found that CDA expression is associated with resistance to drug targeting DNA synthesis. Functional studies demonstrate that overexpressing CDA, and not CDA catalytically inactive mutant, protects PDAC cell lines from camptothecin, a topoisomerase inhibitor, while targeting CDA sensitizes PDAC cells to treatment by camptothecin and oxaliplatin, that forms platinum-DNA adducts. To gain further insights into the clinical potential of such finding, we targeted CDA expression in primary cells from patient with PDAC and found that CDA is essential to primary cell growth, and that CDA targeting sensitizes primary cells to treatment by oxaliplatin. Taken together, our results reveal for the first time that CDA controls DNA replication, replication stress level and genomic stability of PDAC cells, and that this new role of CDA is involved in tumor resistance to drugs inducing DNA damages. Thus, our work stems for new strategies based on CDA targeting to defeat PDAC resistance to treatment. Citation Format: Audrey Lumeau, Nicolas Bery, Cyril Ribeyre, Samad Elkaoutari, Guillaume Labrousse, Miguel Madrid-Mencia, Vera Pancaldi, Marie-Jeanne Pillaire, Valérie Bergoglio, Nelson Dusseti, Jean-Sébastien Hoffmann, Louis Buscail, Malik Lutzmann, Pierre Cordelier. Cytidine deaminase protects pancreatic cancer cells from replicative stress and drive response to DNA-targeting drugs [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2021 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2021;81(22 Suppl):Abstract nr PO-043.