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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 <jats:italic>BRCA2<\/jats:italic>\u2010mutant PDAC cells and identify potential therapeutic targets to modulate this resistance. We developed olaparib\u2010 and talazoparib\u2010resistant Capan\u20101 cell lines and characterised their resistance profiles using viability assays, RNA sequencing and metabolomic profiling. We also developed a cisplatin\u2010resistant Capan\u20101 cell line to compare resistance mechanisms between PARPi and platinum agents. Both olaparib\u2010 and talazoparib\u2010resistant cells showed cross\u2010resistance to other PARPi and oxaliplatin, but not to gemcitabine or 5\u2010FU. Talazoparib\u2010resistant cells exhibited a similar resistance profile to cisplatin\u2010resistant 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\u2010trapping 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.<\/jats:p>","DOI":"10.1111\/jcmm.70816","type":"journal-article","created":{"date-parts":[[2025,8,28]],"date-time":"2025-08-28T11:03:16Z","timestamp":1756378996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Mechanisms of Resistance to <scp>PARPi<\/scp> in Pancreatic Ductal Adenocarcinoma"],"prefix":"10.1111","volume":"29","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8331-1597","authenticated-orcid":false,"given":"Jojanneke","family":"Stoof","sequence":"first","affiliation":[{"name":"Trinity St. James Cancer Institute Trinity College Dublin  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7761-5025","authenticated-orcid":false,"given":"Charlotte","family":"Andrieu","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Life Sciences Institute Dublin City University  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona","family":"O'Connell","sequence":"additional","affiliation":[{"name":"Trinity St. James Cancer Institute Trinity College Dublin  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacintha","family":"O'Sullivan","sequence":"additional","affiliation":[{"name":"Trinity St. James Cancer Institute Trinity College Dublin  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maeve A.","family":"Lowery","sequence":"additional","affiliation":[{"name":"Trinity St. James Cancer Institute Trinity College Dublin  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naomi","family":"Walsh","sequence":"additional","affiliation":[{"name":"School of Biotechnology, Life Sciences Institute Dublin City University  Dublin Ireland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2025,8,28]]},"reference":[{"issue":"1","key":"e_1_2_12_2_1","first-page":"S3","article-title":"Current Treatment Landscape and Emerging Therapies for Pancreatic Cancer","volume":"25","author":"Adel N.","year":"2019","journal-title":"American Journal of Managed Care"},{"issue":"2","key":"e_1_2_12_3_1","first-page":"98","article-title":"Advanced Pancreatic Cancer: The Standard of Care and New Opportunities","volume":"12","author":"Mohammad A. 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