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Mechanisms of Resistance to PARPi in Pancreatic Ductal Adenocarcinoma

Jojanneke Stoof1, Charlotte Andrieu2, Fiona O'Connell1

  • 1Trinity St. James Cancer Institute, Trinity College Dublin, Dublin, Ireland.

Journal of Cellular and Molecular Medicine
|August 28, 2025
PubMed

Insights

Mechanisms of resistance to poly (ADP-ribose) polymerase inhibitors (PARPi) in pancreatic cancer involve metabolic changes. Targeting these metabolic pathways may overcome PARPi resistance in pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

  • Oncology
  • Cancer Biology
  • Drug Resistance

Background:

  • Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis and limited treatment options.
  • Poly (ADP-ribose) polymerase inhibitors (PARPi) show efficacy in PDAC with homologous recombination deficiency (HRD), but resistance limits their use.

Purpose of the Study:

  • To investigate mechanisms of PARPi resistance in BRCA2-mutant PDAC cells.
  • To identify potential therapeutic targets to overcome PARPi resistance.

Main Methods:

  • Developed olaparib- and talazoparib-resistant Capan-1 cell lines.
  • Characterized resistance profiles using viability assays, RNA sequencing, and metabolomic profiling.
  • Developed cisplatin-resistant cells for comparison.

Main Results:

  • Resistant cells showed cross-resistance to other PARPi and oxaliplatin, but not gemcitabine or 5-FU.
  • Talazoparib-resistant cells shared resistance profiles with cisplatin-resistant cells, including decreased PARP1 expression.
  • Enrichment of metabolic pathways (oxidative phosphorylation, glycolysis) was observed in resistant cells.

Conclusions:

  • PARPi resistance in PDAC is complex and linked to metabolic alterations.
  • Metabolic pathways represent potential therapeutic targets to overcome PARPi resistance.
  • PARP-trapping potency may influence resistance development, warranting further investigation.
Keywords:
PARP inhibitorcisplatinmetabolismpancreatic ductal adenocarcinomaresistance

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