Stoof Jojanneke, Andrieu Charlotte, O'Connell Fiona, O'Sullivan Jacintha, Lowery Maeve A, Walsh Naomi
Trinity St. James Cancer Institute, Trinity College Dublin, Dublin, Ireland.
School of Biotechnology, Life Sciences Institute, Dublin City University, Dublin, Ireland.
J Cell Mol Med. 2025 Aug;29(16):e70816. doi: 10.1111/jcmm.70816.
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.
胰腺导管腺癌（PDAC）是一种致死率很高的疾病，治疗选择有限。聚（ADP-核糖）聚合酶抑制剂（PARPi）已显示出在治疗具有同源重组缺陷（HRD）的PDAC方面的潜力，但耐药性的快速产生限制了它们的疗效。我们的目标是研究BRCA2突变的PDAC细胞对PARPi耐药的机制，并确定调节这种耐药性的潜在治疗靶点。我们构建了对奥拉帕利和他拉唑帕利耐药的Capan-1细胞系，并通过活力测定、RNA测序和代谢组学分析来表征它们的耐药特征。我们还构建了对顺铂耐药的Capan-1细胞系，以比较PARPi与铂类药物之间的耐药机制。对奥拉帕利和他拉唑帕利耐药的细胞均对其他PARPi和奥沙利铂表现出交叉耐药性，但对吉西他滨或5-氟尿嘧啶不耐药。对他拉唑帕利耐药的细胞表现出与对顺铂耐药的细胞相似的耐药特征，包括PARP1表达降低和代谢组学特征改变。RNA测序和代谢组学分析揭示了耐药细胞中代谢途径的显著富集，包括氧化磷酸化和糖酵解。我们的研究突出了PDAC中对PARPi耐药机制的复杂性，并确定了代谢方面的潜在治疗靶点。奥拉帕利和他拉唑帕利耐药特征的差异表明，PARP捕获能力可能在耐药性发展中起作用。需要进一步研究来验证这些发现，并探索克服PDAC对PARPi耐药的新治疗策略。
