ArticleJournal of experimental & clinical cancer research : CR2021
Chemotherapy-induced CDA expression renders resistant non-small cell lung cancer cells sensitive to 5'-deoxy-5-fluorocytidine (5'-DFCR).
Article in Journal of experimental & clinical cancer research : CR, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers, 1 of them a synthesis that pooled it.
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12 citing papers in PubMed, 1 synthesis or guideline pooled it, 18 citations in OpenAlex.
- Causal association between plasma proteins and lung adenocarcinoma: a two-sample mendelian randomization study.BMC pulmonary medicine · 2025Pooled it
- Molecular Insights from Differential Proteomic Profiling of Premalignant Cervical Lesions and Cervical Cancer.Pathogens (Basel, Switzerland) · 2026Article
- Metabolic vulnerabilities in pleural mesothelioma.Oncogenesis · 2026Review
- Article
- Deciphering the tumor-suppressive role of RBMS3 in lung adenocarcinoma through genomic insights into prognosis and mechanisms.Scientific reports · 2025Article
- Proteomic profiling of gliomas unveils immune and metabolism-driven subtypes with implications for anti-nucleotide metabolism therapy.Nature communications · 2024Article
- Chemotherapy increases CDA expression and sensitizes malignant pleural mesothelioma cells to capecitabine treatment.Scientific reports · 2024Article
- Downregulation of LRP/LR with siRNA inhibits several cancer hallmarks in lung cancer cells.FEBS open bio · 2023Article
- Schedule-Dependent Treatment Increases Chemotherapy Efficacy in Malignant Pleural Mesothelioma.International journal of molecular sciences · 2022Article
- DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor-resistant lung cancer therapy.Experimental & molecular medicine · 2022Article
- Mechanism of hydroxysafflor yellow A on acute liver injury based on transcriptomics.Frontiers in pharmacology · 2022Article
- Aldolase A and Phospholipase D1 Synergistically Resist Alkylating Agents and Radiation in Lung Cancer.Frontiers in oncology · 2021Article
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Authors and funding
15 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundPemetrexed (MTA) plus cisplatin combination therapy is considered the standard of care for patients with advanced non-small-cell lung cancer (NSCLC). However, in advanced NSCLC, the 5-year survival rate is below 10%, mainly due to resistance to therapy. We have previously shown that the fraction of mesenchymal-like, chemotherapy-resistant paraclone cells increased after MTA and cisplatin combination therapy in the NSCLC cell line A549. Cytidine deaminase (CDA) and thymidine phosphorylase (TYMP) are key enzymes of the pyrimidine salvage pathway. 5'-deoxy-5-fluorocytidine (5'-DFCR) is a cytidine analogue (metabolite of capecitabine), which is converted by CDA and subsequently by TYMP into 5-fluorouracil, a chemotherapeutic agent frequently used to treat solid tumors. The aim of this study was to identify and exploit chemotherapy-induced metabolic adaptations to target resistant cancer cells.
methodsCell viability and colony formation assays were used to quantify the efficacy of MTA and cisplatin treatment in combination with schedule-dependent addition of 5'-DFCR on growth and survival of A549 paraclone cells and NSCLC cell lines. CDA and TYMP protein expression were monitored by Western blot. Finally, flow cytometry was used to analyze the EMT phenotype, DNA damage response activation and cell cycle distribution over time after treatment. CDA expression was measured by immunohistochemistry in tumor tissues of patients before and after neoadjuvant chemotherapy.
resultsWe performed a small-scale screen of mitochondrial metabolism inhibitors, which revealed that 5'-DFCR selectively targets chemotherapy-resistant A549 paraclone cells characterized by high CDA and TYMP expression. In the cell line A549, CDA and TYMP expression was further increased by chemotherapy in a time-dependent manner, which was also observed in the KRAS-addicted NSCLC cell lines H358 and H411. The addition of 5'-DFCR on the second day after MTA and cisplatin combination therapy was the most efficient treatment to eradicate chemotherapy-resistant NSCLC cells. Moreover, recovery from treatment-induced DNA damage was delayed and accompanied by senescence induction and acquisition of a hybrid-EMT phenotype. In a subset of patient tumors, CDA expression was also increased after treatment with neoadjuvant chemotherapy.
conclusionsChemotherapy increases CDA and TYMP expression thereby rendering resistant lung cancer cells susceptible to subsequent 5'-DFCR treatment.
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