Oxaliplatin Compromised CDK1 Activity Sensitizes BRCA-Proficient Cancers to PARP Inhibition in Oxaliplatin Resistance Gastric Cancer

Abstract Background: Oxaliplatin resistance is one of the most important problems in the treatment of cancer. The successful culture of tumor organoid in gastric cancer can help us to study oxaliplatin resistance and its mechanism. Thus, it is convenient for us to successfully solve oxaliplatin resistance and improve the prognosis of patients.Methods: Two oxaliplatin resistant patients and two oxaliplatin sensitive patients were enrolled through our Gastric Cancer Center of Sun Yat-sen University. Core genes of oxaliplatin resistant and non-resistant patients were analyzed by sequencing. The overexpression and knockdown of core genes were carried out by organoid in vivo, combined with oxaliplatin-resistant cell lines AGS, MKN74 and SNU719 for cell viability, WB and immunofluorescence, etc., to verify the role of core genes in oxaliplatin resistance. Again, in vivo experiments were verified by subcutaneous tumor formation in vitro.Results: Through sequencing, we found that PARP1 is an important core gene leading to oxaliplatin resistance. In vivo organoids, oxaliplatin resistant cell lines and subcutaneous tumor formation in vivo. We found that PARP1 was an important cause of oxaliplatin resistance. Oxaliplatin can inhibit CDK1 activity and make cancer with normal BRCA1 function sensitive to PARP inhibition. Through the combination of oxaliplatin and PARP1 inhibitor olaparib, we can effectively kill tumor cells. Through the patients' follow-up data, we found that the expression level of PARP1 was significantly correlated with oxaliplatin resistance.Conclusion: Our results indicate that PARP1 is an important core gene leading to oxaliplatin resistance. Combined oxaliplatin and PARP1 inhibitor olaparib can effectively kill tumor cells. Oxaliplatin can inhibit CDK1 activity and make cancers with normal BRCA1 function more sensitive to PARP inhibitors.