Abstract
BackgroundResistance 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.ResultsResistant 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.ConclusionsChromatin 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.
Highlights
Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis
Using matched chemosensitive and chemoresistant ovarian cancer cell lines isolated from high-grade serous ovarian cancer patients before and following treatment, we examined the relationship between chromatin accessibility, platinum-DNA adduct distribution, and chemotherapy resistance
PEO1 and PEO4 were both isolated from the same patient diagnosed with high-grade serous ovarian cancer (HGSOC) following platinum-based chemotherapy, but before and after the clinical development of resistance [25]
Summary
Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. Platinum-based chemotherapeutics, such as cisplatin and carboplatin, are clinically important first line therapies in the treatment of a wide variety of solid cancers [1, 2]. These drugs exert their DNA damaging, cytotoxic effect by the formation of platinum-DNA adducts, inter- and intra-strand cross-links, which induce cell death through a number of pathways if the adduct is not repaired [3]. Drug-tolerant persisters exhibit a repressed chromatin state and can serve as founders for further genetic and epigenetic change leading to resistance [7, 9,10,11]. The promoters of genes susceptible to hypermethylation in ovarian tumors during the emergence of resistance
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
