Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with BRCA1/2 gene mutations or additional homologous recombination (HR) DNA repair pathway deficiencies. These defects serve as biomarkers for response to PARP inhibitors (PARPi). We sought to identify an additional biomarker that could predict responses to both conventional chemotherapy and PARPi in ovarian cancers. We focused on cellular ADP-ribosylation (ADPRylation), which is catalyzed by PARP enzymes and detected by detection reagents we developed previously. We determined molecular phenotypes of 34 high-grade serous ovarian cancers and associated them with clinical outcomes. We used the levels and patterns of ADPRylation and PARP-1 to distribute ovarian cancers into distinct molecular phenotypes, which exhibit dramatically different gene expression profiles. In addition, the levels and patterns of ADPRylation, PARP-1 protein, and gene expression correlated with clinical outcomes in response to platinum-based chemotherapy, with cancers exhibiting the highest levels of ADPRylation having the best outcomes independent of BRCA1/2 status. Finally, in cell culture-based assays using patient-derived ovarian cancer cell lines, ADPRylation levels correlated with sensitivity to the PARPi, Olaparib, with cell lines exhibiting high levels of ADPRylation having greater sensitivity to Olaparib. Collectively, our study demonstrates that ovarian cancers exhibit a wide range of ADPRylation levels, which correlate with therapeutic responses and clinical outcomes. These results suggest ADPRylation may be a useful biomarker for PARPi sensitivity in ovarian cancers, independent of BRCA1/2 or homologous recombination deficiency status.

中文翻译：

---

ADP-核糖基化水平和模式与卵巢癌的基因表达和临床结果相关

核 PARP 酶抑制剂（例如，PARP-1）改善了卵巢癌的临床结果，尤其是在 BRCA1/2 基因突变或其他同源重组 (HR) DNA 修复途径缺陷的患者中。这些缺陷可作为对 PARP 抑制剂 (PARPi) 反应的生物标志物。我们试图确定一种额外的生物标志物，它可以预测卵巢癌对常规化疗和 PARPi 的反应。我们专注于细胞 ADP-核糖基化 (ADPRylation)，它由 PARP 酶催化并由我们之前开发的检测试剂检测。我们确定了 34 种高级别浆液性卵巢癌的分子表型，并将它们与临床结果相关联。我们使用 ADPRylation 和 PARP-1 的水平和模式将卵巢癌分布为不同的分子表型，表现出截然不同的基因表达谱。此外，ADPRylation、PARP-1 蛋白和基因表达的水平和模式与铂类化疗的临床结果相关，表现出最高水平的 ADPRylation 的癌症具有独立于 BRCA1/2 状态的最佳结果。最后，在使用患者来源的卵巢癌细胞系的基于细胞培养的测定中，ADPRylation 水平与对 PARPi、Olaparib 的敏感性相关，表现出高水平 ADPRylation 的细胞系对 Olaparib 具有更高的敏感性。总的来说，我们的研究表明，卵巢癌表现出广泛的 ADPRylation 水平，这与治疗反应和临床结果相关。