Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance

Background Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy. Results Resistant lines show altered chromatin accessibility at intergenic regions, but less so at gene promoters. Clusters of cis-regulatory elements at these intergenic regions show chromatin changes that are associated with altered expression of linked genes, with enrichment for genes involved in the Fanconi anemia/BRCA DNA damage response pathway. Further, genome-wide distribution of platinum adducts associates with the chromatin changes observed and distinguish sensitive from resistant lines. In the resistant line, we observe fewer adducts around gene promoters and more adducts at intergenic regions. Conclusions Chromatin changes at intergenic regulators of gene expression are associated with in vivo derived drug resistance and Pt-adduct distribution in patient-derived HGSOC drug resistance models.

Automated summary

The genomic distribution of accessible chromatin sites is altered in cisplatin-resistant ovarian cell lines from high grade serous ovarian cancer patients, with changes at intergenic regions associated with gene expression and resistance mechanisms. The distribution of platinum adducts correlates with chromatin changes and distinguishes between sensitive and resistant cell lines, with fewer adducts around gene promoters and more at intergenic regions in resistant cells. These findings highlight the role of chromatin changes in gene regulation in the development of drug resistance in ovarian cancer.