Mechanisms of Resistance to PARPi in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly fatal disease with limited treatment options. PARP inhibitors (PARPi) have shown promise in treating PDAC with homologous recombination deficiency (HRD), but rapid acquisition of resistance limits their efficacy. Our objective is to investigate mechanisms of resistance to PARPi in BRCA2-mutant PDAC cells and identify potential therapeutic targets to modulate this resistance. We developed olaparib- and talazoparib-resistant Capan-1 cell lines and characterised their resistance profiles using viability assays, RNA sequencing and metabolomic profiling. We also developed a cisplatin-resistant Capan-1 cell line to compare resistance mechanisms between PARPi and platinum agents. Both olaparib- and talazoparib-resistant cells showed cross-resistance to other PARPi and oxaliplatin, but not to gemcitabine or 5-FU. Talazoparib-resistant cells exhibited a similar resistance profile to cisplatin-resistant cells, including decreased PARP1 expression and altered metabolomic profiles. RNA sequencing and metabolomic profiling revealed significant enrichment of metabolic pathways, including oxidative phosphorylation and glycolysis, in resistant cells. Our study highlights the complexity of resistance mechanisms to PARPi in PDAC and identifies potential therapeutic targets in metabolism. The differences in the resistance profiles between olaparib and talazoparib suggest that PARP-trapping potency may play a role in resistance development. Further research is needed to validate these findings and explore novel therapeutic strategies to overcome resistance to PARPi in PDAC.