Dr Pierre Cordelier, PhD in Human Physiopathology, is Research Director at INSERM, team leader (ther-apeutic innovation in pancreatic cancer) and deputy director of the cancer research centre of Toulouse(CRCT). Dr Cordelier research focus is to identify the molecular mechanisms involved into pancreatictumors oncogenesis and resistance to treatment, to advocate for personalized therapies and help alle-viate the dismal prognosis of this disease with no cure.
The objective of this research program is to identify the role of cytidine deaminase, an enzyme otherwise involved in tumor resistance to gemcitabine, is exerting in pancreatic cancer cells
Chronic DNA replication stress and genome instability are two hallmarks of cancer that fuel oncogene sis and tumor diversity. Therapeutic approaches aimed to leverage tumor-specific replication stress to intolerable levels or to expose vulnerabilities for synthetic lethality purpose have recently gained mo mentum, especially for pancreatic cancer, a disease with no cure. However, the current knowledge is limited considering the molecular mechanisms involved in the replication stress response in pancreat ic tumors. Cytidine deaminase (CDA) is involved in the pyrimidine salvage pathway for DNA and RNA synthesis. Loss of CDA induces genomic instability in Bloom Syndrome, and CDA protects tumor cells from chemotherapy with pyrimidine analogs. Here, we show that CDA is overexpressed in genetically instable pancreatic tumors, associates with DNA replication signature and is instrumental for experi mental tumor growth. In cancer cells, CDA promotes DNA replication, increases replication fork fitness for controlling replication stress and genomic stability. CDA expression is predictive of DNA-damaging drug efficacy, and targeting CDA relieves resistance to chemotherapy in patients’ models. Our findings shed a new light on the mechanisms by which pancreatic cancer cells control replication stress, and highlight targeting of CDA as a potential therapeutic intervention to defeat tumor resistance to treat ment.
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