DNA Repair and Response to Therapy: Exploring their Relation in Epithelial Ovarian Cancer Models

Guffanti, Federica (2021). DNA Repair and Response to Therapy: Exploring their Relation in Epithelial Ovarian Cancer Models. PhD thesis The Open University.

DOI: https://doi.org/10.21954/ou.ro.0001278a

Abstract

Epithelial ovarian cancer (EOC) is often characterized by defects in DNA repair pathways, which partially explain its sensitivity to platinum compounds and to poly (ADP-ribose) polymerase inhibitors (PARPi). However, EOC almost invariably relapses with a drug resistant, incurable disease. Biomarkers able to predict the response to therapy could ameliorate the management of EOC patients.

The studies herein reported aimed to elucidate the role of different DNA repair pathways as possible determinants of cisplatin (DDP) and olaparib (a PARPi) response in a collection of patient-derived xenografts (PDXs) characterized for their response to both drugs. We analysed the expression of 35 different DNA repair genes involved in DDP and olaparib response, and found CDK12, XPF, PALB2, USP28, ARTEMIS, ARID1A and MDR1 associated with DDP response. In particular, CDK12 expression was significantly higher in DDP resistant PDXs and associated with higher recurrence rate in EOC patients with low residual tumour. We analysed the basal level of RAD51 foci in proliferating cells of formalin-fixed paraffin-embedded PDX tumours, as possible readout of homologous recombination pathway, and found that the percentage of RAD51 foci-positive cells predicted olaparib, but not DDP response. As DDP adducts can be repaired by multiple pathways including nucleotide excision repair (NER) and base excision repair (BER), we studied POLB, ERCC1, XPF and ERCC1/XPF complex as read out of NER and BER activity, but no correlation with DDP response was found.

These findings support the role of CDK12 and RAD51 foci expressed in untreated tumours in the response to DDP and olaparib, respectively, in our EOC PDX models and warrant the setup of DNA repair functional assays able to capture the complexity of factors determining DDP and PARPi response, that could be easily translated in the clinical practice to prioritize treatment choice in EOC patients.

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