ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers

• Type of Material: Article
• Authors: Lesley Conrad, Emory University; Ken Y. Lin, University of Texas Southwestern Medical Center; Tulip Nandu, University of Texas Southwestern Medical Center; Bryan A. Gibson, University of Texas Southwestern Medical Center; Jayanthi S. Lea, University of Texas Southwestern Medical Center; W. Lee Kraus, University of Texas Southwestern Medical Center
• Language: English
• Date: 2020-01-01
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 American Association for Cancer Research.
• Final Published Version (URL): http://dx.doi.org/10.1158/1535-7163.MCT-19-0569
• Title of Journal or Parent Work: Molecular Cancer Therapeutics
• Volume: 19
• Issue: 1
• Start Page: 282
• End Page: 291
• Grant/Funding Information: This work was supported by a grant from the NIH/NIDDK (R01 DK069710) and funds from the Cecil H. and Ida Green Center for Reproductive Biology Sciences Endowment to W.L.K.
• Keywords: Oncology; Cells; Sensitivity; ABT-888; Ribose polymerase; Poly(ADP-Ripose) polymerase; Olaparib; Science & Technology; Nonparametric estimation; Maintenance therapy; Parp inhibitors; Life Sciences & Biomedicine; Tumors
• Research Categories: Biology, Genetics; Health Sciences, Oncology; Biology, Cell; Health Sciences, Obstetrics and Gynecology

Abstract

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.