Cumulative defects in DNA repair pathways drive the PARP inhibitor response in high-grade serous epithelial ovarian cancer cell lines.

Hubert Fleury,Jean-Yves Masson,Vincent G Morin,Anne-Marie Mes-Masson,Liliane Meunier,Patricia N Tonin,Euridice Carmona,Diane Provencher

doi:10.18632/oncotarget.10308

Abstract

PARP inhibitors (PARPi), such as Olaparib, have shown promising results in high-grade serous (HGS) epithelial ovarian cancer (EOC) treatment. PARPi sensitivity has been mainly associated with homologous recombination (HR) deficiency, but clinical trials have shown that predicting actual patient response is complex. Here, we investigated gene expression microarray, HR functionality and Olaparib sensitivity of 18 different HGS EOC cell lines and demonstrate that PARPi sensitivity is not only associated with HR defects. Gene target validation show that down regulation of genes in the nucleotide excision repair (NER) and mismatch repair (MMR) pathways (ERCC8 and MLH1, respectively) increases PARPi response. The highest sensitivity was observed when genes in both the HR and either NER or MMR pathways were concomitantly down regulated. Using clinical samples, patients with these concurrent down regulations could be identified. Based on these results, a novel model to predict PARPi sensitivity is herein proposed. This model implies that the extreme responders identified in clinical trials have deficiencies in HR and either NER or MMR.

Highlights

Ovarian cancer is the most lethal of all gynecologic malignancies in North America [1]
high-grade serous (HGS) epithelial ovarian cancer (EOC) cell lines can be distinguished into three groups of Olaparib sensitivity To better understand the poly (ADP-ribose) polymerase inhibitors (PARPi) response in HGS EOC, we used our unique collection of 18 HGS EOC cell lines derived from malignant tumors (TOV-) and ascites (OV-)
PARP1 synthesizes PAR chains that covalently bind a variety of chromatin-associated proteins, PARP1 itself is the major acceptor of the PAR chains

Summary

Introduction

Ovarian cancer is the most lethal of all gynecologic malignancies in North America [1] This is attributed to the asymptomatic nature of the disease, resulting in a late stage diagnosis with a five-year survival rate of 45% [1]. PARPi were first introduced to treat breast cancer patients harboring germline BRCA1/ BRCA2 mutations based on the synthetic lethality context, where it has been proposed that a defect in one repair pathway is compatible with cell viability but results in cell death when combined with another repair pathway defect or inhibition [10]. Several models have been proposed to explain the synthetic lethality of HR-deficient cells to the PARPi, due to the complex role of the PARP1 polymerase in repairing single and double strand DNA breaks, the complete mechanism is still not understood [8, 9]

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Conclusion