Clinicopathological and functional evaluation of replication protein A in epithelial ovarian cancers: A target validation study

TL;DR

This study shows that high levels of RPA in ovarian cancer are linked to aggressive disease and drug resistance, and reducing RPA makes cancer cells more sensitive to treatment.

Contribution

The study validates RPA as a potential therapeutic target in high-grade serous ovarian cancer.

Findings

High RPA1 and RPA2 levels correlate with advanced stage, platinum resistance, and worse survival in ovarian cancer.

Reducing RPA increases sensitivity to platinum and PARP inhibitors in preclinical models.

HAMNO, an RPA inhibitor, shows cytotoxic effects in both sensitive and resistant cancer cells.

Abstract

•Replication Protein A (RPA), a single-stranded DNA (ssDNA)-binding protein is critically involved in DNA replication, checkpoint regulation and DNA repair.•Comprehensive protein and transcriptomic evaluation show that RPA overexpression is linked with aggressive ovarian cancer and platinum resistance.•RPA depletion promoted platinum and PARP inhibitor sensitivity.

Replication Protein A (RPA), a single-stranded DNA (ssDNA)-binding protein is critically involved in DNA replication, checkpoint regulation and DNA repair.

Comprehensive protein and transcriptomic evaluation show that RPA overexpression is linked with aggressive ovarian cancer and platinum resistance.

RPA depletion promoted platinum and PARP inhibitor sensitivity.

Replication Protein A (RPA), a single-stranded DNA (ssDNA)-binding protein is critically involved in DNA replication, checkpoint regulation and DNA repair. We evaluated RPA1, 2, and 3 sub-units protein expression in 331 ovarian tumours, transcripts in 1287 tumours and bioinformatics in the ovarian TCGA cohort (n = 379). Platinum resistant ovarian cancer cells were depleted for RPA 1 or 2 and tested for cisplatin, olaparib and talazoparib sensitivity. HAMNO (RPA1 protein-protein interaction inhibitor) was tested in sensitive and resistant cells. High nuclear RPA1 and RPA2 protein was significantly associated with high grade serous ovarian cancers (HGSOC), advanced stage, platinum resistance and worse progression free survival (PFS) (all ps <0.05). High RPA1 and RPA2 transcripts also linked with poor PFS. Preclinically, RPA1 or RPA 2 depletion increased sensitivity to cisplatin, olaparib and talazoparib treatment. HAMNO monotherapy was cytotoxic to sensitive and resistant cells. We conclude that RPA directed precision oncology strategy could be a viable strategy in HGSOC.

Figures