High-grade serous ovarian cancer (HGSC) is the most common and lethal subtype of ovarian cancer. Debulking surgery is the primary treatment, supplemented by platinum and taxane combination chemotherapy. The response to treatment is generally good, but most patients eventually develop drug resistance, leading to disease progression and death. Nevertheless, the treatment strategy has remained relatively unchanged, and overall survival has hardly improved over the last 20 years.

The primary events in early HGSC development are the inactivation of the tumor suppressor p53, and the homologous recombination pathway, which results in a severely damaged genome and allows the development of individual cancer cell clones. Genomic rearrangements, including gene fusions may evolve, when two separate genes join to form a new gene product. Genes can also fuse at the RNA level due to splicing. The functional changes in fusion proteins and chimeric RNAs can cause cancer initiation, tumor progression, and drug resistance.

HGSC is a genetically unstable disease in which fusions are very common. Poor treatment outcomes can be associated with the emergence of treatment-resistant subclones. Deep sequencing has significantly increased the knowledge of the molecular characteristics of HGSC. Understanding the genomic and non-genomic abnormalities of HGSC tumors will help design personalized therapeutic approaches and discover novel mechanisms of drug resistance. However, at present, the role of gene fusions in HGSC is poorly studied.

This Ph.D. thesis aimed to identify new potential drug targets for ovarian cancer patients. Using computational modeling, we identified 228 novel fusion genes from 107 cancer samples of 36 HGSC patients. We demonstrated by laboratory experiments the presence of the most biologically interesting fusions in cancer cells. Furthermore, we investigated the PIK3R1-CCDC178 fusion protein and its role as a tumor-promoting alteration and impact on drug response. The fusion induced HGSC cell migration and resistance to platinum and trametinib treatment through ERK1/2 activation but the fusion-expressing cells remained sensitive to the combination of the treatments. Therapy resistance was associated with rod and ring-like cellular structure formation.