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

Lesley B. Conrad, Ken Y. Lin, Tulip Nandu, Bryan A. Gibson, Jayanthi S. Lea, W. Lee Kraus

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)282-291
Number of pages10
JournalMolecular cancer therapeutics
Volume19
Issue number1
DOIs
StatePublished - Jan 1 2020

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Ovarian Neoplasms
Adenosine Diphosphate
Gene Expression
Biomarkers
DNA Repair-Deficiency Disorders
BRCA1 Gene
Phenotype
Recombinational DNA Repair
Drug Therapy
Cell Line
Homologous Recombination
Enzymes
Platinum
Transcriptome
Cell Culture Techniques
Poly(ADP-ribose) Polymerase Inhibitors
Mutation
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers. / Conrad, Lesley B.; Lin, Ken Y.; Nandu, Tulip; Gibson, Bryan A.; Lea, Jayanthi S.; Kraus, W. Lee.

In: Molecular cancer therapeutics, Vol. 19, No. 1, 01.01.2020, p. 282-291.

Research output: Contribution to journalArticle

Conrad, Lesley B. ; Lin, Ken Y. ; Nandu, Tulip ; Gibson, Bryan A. ; Lea, Jayanthi S. ; Kraus, W. Lee. / ADP-Ribosylation Levels and Patterns Correlate with Gene Expression and Clinical Outcomes in Ovarian Cancers. In: Molecular cancer therapeutics. 2020 ; Vol. 19, No. 1. pp. 282-291.
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