High-grade serous
ovarian cancer is the most common ovarian cancer type. Although the combination
of surgery and platinum-taxane chemotherapy provide an effective treatment,
drug resistance frequently occurs leading to poor outcome. In order to clarify
the molecular mechanisms of drug resistance, the DNA methylation and
transcriptomic changes, associated with the development of drug resistance in
high-grade serous ovarian cancer, were examined from patient derived malignant ascites
cells. In parallel with large-scale transcriptome
changes, cisplatin resistance was associated with loss of hypermethylation at
several CpG sites primarily localized in the intergenic regions of the genome.
The transcriptome and CpG methylome changes in response to cisplatin treatment
of both sensitive and resistant cells were minimal, indicating the importance
of post-translational mechanisms in regulating death or survival of the cells. The
response of resistant cells to high concentrations of cisplatin revealed
transcriptomic changes in potential key drivers of drug resistance, such as KLF4. Among the strongest changes was induction
of IL6 in the resistant cells, with
its expression further increased in response to cisplatin. Also, several other
components of IL6 signaling were affected, further supporting previous
observations on its importance in malignant transformation and development of
drug resistance in ovarian cancer.