Cell Cycle Reprogramming Mediates Acquired Oxaliplatin Resistance in Pancreatic Cancer.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a lethal malignancy with limited treatment options. While oxaliplatin-based (Oxa) therapy, such as FOLFIRINOX, has improved outcomes in select patients, Oxa resistance significantly limits its efficacy. This study investigates cell cycle mechanisms driving Oxa resistance and explores targeting these pathways as a therapeutic strategy. Experimental Design: Murine KPC and human Panc1 oxaliplatin-resistant (Oxa-R) cell lines were established. RNA sequencing, Western blotting, and flow cytometry were used to analyze DNA damage and cell cycle regulators. Viability assays and a murine orthotopic PDAC model were employed to evaluate the therapeutic potential of CDK4/6 inhibition with Oxa. 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.