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

Overview

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.