Identification of New Regulators of Pancreatic Cancer Cell Sensitivity to Oxaliplatin and Cisplatin

• Published in: Molecules (Basel, Switzerland) Switzerland), 2022-02, Vol.27 (4), p.1289
• Main Authors: Skripova, Vera, Vlasenkova, Ramilia, Zhou, Yan, Astsaturov, Igor, Kiyamova, Ramziya
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - pharmacology; Binding; Bioinformatics; Biomarkers; Biomarkers, Tumor; Cancer therapies; Cell cycle; Cell Line, Tumor; Chemoresistance; Chemotherapy; chemotherapy resistance; Cisplatin; Cisplatin - pharmacology; Communication; Computational Biology - methods; CRISPR; CRISPR-Cas Systems; CRISPR/Cas9 screening; Dehydrogenases; Deoxyribonucleic acid; Disease; DNA; DNA repair; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Drug Screening Assays, Antitumor; Drugs; Enrichment; Gene Expression Profiling; Gene Knockdown Techniques; Gene Ontology; Gene Regulatory Networks; Genes; Genomes; Humans; In vivo methods and tests; Mutation; NADH; NADH dehydrogenase; Ontology; Oxaliplatin; Oxaliplatin - pharmacology; Pancreatic cancer; Pancreatic Neoplasms; Platinum; Regulation; Serology; Single-stranded DNA; Synthetic Lethal Mutations; Tumor cells
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules27041289

The chemoresistance of tumor cells is one of the most urgent challenges in modern oncology and in pancreatic cancer, in which this problem is the most prominent. Therefore, the identification of new chemosensitizing co-targets may be a path toward increasing chemotherapy efficacy. In this work, we performed high-performance in vitro knockout CRISPR/Cas9 screening to find potential regulators of the sensitivity of pancreatic cancer. For this purpose, MIA PaCa-2 cells transduced with two sgRNA libraries ("cell cycle/nuclear proteins genes" and "genome-wide") were screened by oxaliplatin and cisplatin. In total, 173 candidate genes were identified as potential regulators of pancreatic cancer cell sensitivity to oxaliplatin and/or cisplatin; among these, 25 genes have previously been reported, while 148 genes were identified for the first time as potential platinum drug sensitivity regulators. We found seven candidate genes involved in pancreatic cancer cell sensitivity to both cisplatin and oxaliplatin. Gene ontology enrichment analysis reveals the enrichment of single-stranded DNA binding, damaged DNA binding pathways, and four associated with NADH dehydrogenase activity. Further investigation and validation of the obtained results by in vitro, in vivo, and bioinformatics approaches, as well as literature analysis, will help to identify novel pancreatic cancer platinum sensitivity regulators.