Laboratory of Signaling and Gene Expression, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
Division of Basic Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.
Mol Cancer Ther. 2020 Jan;19(1):282-291. doi: 10.1158/1535-7163.MCT-19-0569. Epub 2019 Oct 8.
Inhibitors of nuclear PARP enzymes (e.g., PARP-1) have improved clinical outcomes in ovarian cancer, especially in patients with 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 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 or homologous recombination deficiency status.
核 PARP 酶抑制剂（如 PARP-1）已改善了卵巢癌的临床结局，特别是在具有 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。我们试图确定另一种生物标志物，可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，并通过我们之前开发的检测试剂进行检测。我们确定了 34 例高级别浆液性卵巢癌的分子表型，并将其与临床结局相关联。我们使用 ADPRylation 和 PARP-1 的水平和模式将卵巢癌分为不同的分子表型，这些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对铂类化疗的临床反应相关，表现出最高 ADPRylation 水平的癌症具有独立于 状态的最佳结局。最后，在使用患者来源的卵巢癌细胞系进行的基于细胞培养的测定中，ADPRylation 水平与 PARPi（奥拉帕利）的敏感性相关，表现出高水平 ADPRylation 的细胞系对奥拉帕利更敏感。总之，我们的研究表明卵巢癌表现出广泛的 ADPRylation 水平，与治疗反应和临床结局相关。这些结果表明 ADPRylation 可能是卵巢癌对 PARPi 敏感性的有用生物标志物，独立于 或同源重组缺陷状态。
