Investigating Mechanisms of Intrinsic Chemoresistance in High Grade Serous Ovarian Cancer

Abstract

High grade serous ovarian cancer (HGSOC) is the most common type of ovarian cancer (OC) and is responsible for the most OC deaths. Poor long-term survival in HGSOC patients is due to late-stage diagnosis and resistance to chemotherapy (chemoresistance). At 1st line, HGSOC patients are typically treated with combinatory carboplatin and paclitaxel chemotherapy. However, there is currently no way to identify patients who will not respond, or respond extremely poorly, to 1st line chemotherapy nor are there any alternative treatment options for these intrinsically chemoresistant patients. This project aimed to identify markers and mechanisms of intrinsic chemoresistance in HGSOC. To do this, primary ascites-derived cell lines established from intrinsically resistant and inherently sensitive HGSOC patients underwent RNA sequencing (RNAseq) analysis and expression was compared by differential gene expression (DGE) analysis. Ten ‘candidate resistance genes’ were established from genes found significantly upregulated in the intrinsically resistant patients. Only the expression of SPOCK2 was significantly associated with both survival and platinum resistance status in an external HGSOC patient genomic dataset. Individually reducing the expression of each candidate resistance gene in select HGSOC cell lines via siRNA knockdown (KD) did not significantly alter sensitivity to carboplatin. Interexperiment variability means that further experimental replicates, including confirmation of protein-level reduction upon KD, are needed to confirm that these genes do not promote chemoresistance in HGSOC. The expression of a subset of candidate resistance genes were later found to not be associated with resistance status in a similar patient cohort from which they were established. Collectively, limitations in the initial RNAseq DGE analysis, lack of external validation, and negative results in the in vitro cell line experiments, meant that no genes could confidently be attributed to intrinsic chemoresistance in HGSOC. Using the results of a RNAseq study previously carried out in our group, 6 of the candidate resistance genes were found upregulated in HGSOC patients who acquired resistance to chemotherapy following initial sensitivity. Five of these genes were also upregulated in resistant PEA2 cells compared to matched sensitive PEA1 cells, warranting further investigation into their role in acquired chemoresistance.

Date of Award	2025
Original language	English
Awarding Institution	University of Dundee
Supervisor	Gillian Smith (Supervisor), Michelle Ferguson (Supervisor) & Albena Dinkova-Kostova (Supervisor)