Exploring the interaction of DNA repair pathways in ovarian cancer

Abstract

The dysregulation of DNA damage repair has a significant clinical impact in ovarian cancer. DNA double strand breaks (DSB) are repaired by the homologous recombination (HR) and the non homologous end joining (NHEJ) pathways. 50 % of ovarian cancers are HR defective (HRD), which makes these cancers sensitive to poly(ADP-ribose) polymerase inhibitors (PARPi). The role of PARP-1 in NHEJ, and the interaction between the two pathways in cancer chemo- and radio-sensitivity has been reported. In this study, a primary ovarian cancer (PCO) culture model, derived from ascites, was optimised and the association of HRD with PARPi and cisplatin sensitivity confirmed. One PCO culture spontaneously immortalised, forming a novel cell line, NUOC-1, which was characterised demonstrating extensive genomic instability, clonal evolution and genomic aberrations consistent with an endometrioid / clear cell ovarian cancer. NHEJ was found to be defective in 40 % of ovarian cancers, which was independent of HR and was associated with resistance to the PARPi, rucaparib. DNA-PKcs, Ku70 and Ku80 were found to be promising biomarkers for NHEJ function, however utility may be limited by intra-tumour heterogeneity. The role of PARP-1 in DNA DSB recognition and repair was assessed. Whilst PARP-1 expression and activity were independent of HR and NHEJ, PARP-1 was found to interact with DNA-PK and ATR in DSB recognition and repair. HR recovery was found to lead to cisplatin and rucaparib cross resistance, and this appeared to be independent of BRCA and NHEJ function. Additionally, cisplatin resistant HRD cells were found to remain sensitive to rucaparib. Mutational and gene expression profiles were found to be cell and drug dependent with complex alterations in all resistant cell lines. These results demonstrate the essential role of DSBs repair pathways in platinum and PARPi sensitivity. Stratification of tumours by HR and NHEJ function may therefore improve patient selection for treatment.