Regulation of acquired drug resistance by mirnas in high grade serous ovarian cancer

Epithelial ovarian cancer is the seventh most common malignancy diagnosed in women worldwide and the fifth most common cause of cancer-related deaths. Limited improvements in outcomes have been made over the past decades, and the relative five-year survival rate is less than 50%. High-grade serous ovarian cancer (HGSOC) is the predominant histological subtype. PARP inhibitors such as Olaparib (Lynparza™), and niraparib (Zejula™) have been approved for the treatment of platinum sensitive, recurrent HGSOC. However, like many other targeted agents, the efficacy of PARP inhibitors is limited by the development of drug resistance. miRNAs are small (21-23 nucleotide long) non-coding RNA molecules that play a role in post-translational regulation of gene expression. Several cellular pathways are affected by miRNAs, such as cell differentiation, proliferation, and apoptosis. The aim of this project is to explore the role of miRNAs in the context of treatment response and resistance in high grade serous ovarian cancer. To this end, drug resistant HGSOC cells established with ex vivo cultures of primary cells obtained from resistant (patients with poor prognosis after maximal cytoreductive surgery) and sensitive (patients with good prognosis after maximal cytoreductive surgery) patients diagnosed with HGSOC to investigate the underlying mechanisms of drug resistance towards clinically used drugs. 188-5p gene expression level was found significantly downregulated in Olaparib resistant OVCAR-3 cells and resistant FFPE patient samples with poor prognosis after cytoreductive surgery. Combinational treatment studies showed that synergistic effect of Olaparib and 188-5p mimic decreased the survival rate of the resistant cells. Downstream effects of synergistic treatment of the 188-5p mimic and Olaparib exhibited an increase in caspase-8 mediated apoptosis levels in resistant cells. Moreover, in cell cycle experiments, subG1 arrest was observed upon 188-5p transfection. Results revealed that upregulating mir188-5p level in resistant cells significantly suppressed the epithelial-to-mesenchymal transition of resistant cells by decreasing N-cadherin and SNAIL and increasing E-cadherin protein levels.