Cell Cycle Reprogramming Mediates Acquired Oxaliplatin Resistance in Pancreatic Cancer.

Results: Oxa-R cell lines exhibited slower proliferation rates, reduced response to Oxa treatment, and significant upregulation of G2/M and E2F1 signaling pathways, findings that correlated with poor survival outcomes in human clinical datasets. In Oxa-sensitive PDAC cells, Oxa treatment activated the ATR-Chk1 pathway, leading to cyclin D1 suppression and apoptosis. In contrast, Oxa resistance was characterized by compensatory upregulation of CDK4/6 signaling, which enabled cells to bypass DNA damage-induced cell cycle arrest.

Notably, the addition of CDK4/6 inhibitors restored Oxa sensitivity in resistant cell lines, resulting in enhanced apoptosis in vitro and significantly reduced tumor growth in vivo. Conclusion: Oxa resistance in PDAC is mediated by cell cycle dysregulation involving cyclin D1 and CDK4/6. Targeting CDK4/6 with Abemaciclib reverses resistance and enhances Oxa efficacy, offering a promising therapeutic strategy for resistant PDAC.