Abstract
There is a lack of personalized treatment options for women with recurrent platinum-resistant ovarian cancer. Outside of bevacizumab and a group of poly ADP-ribose polymerase inhibitors, few options are available to women that relapse. We propose that efficacious drug combinations can be determined via molecular characterization of ovarian tumors along with pre-established pharmacogenomic profiles of repurposed compounds. To that end, we selectively performed multiple two-drug combination treatments in ovarian cancer cell lines that included reactive oxygen species inducers and HSP90 inhibitors. This allowed us to select cell lines that exhibit disparate phenotypes of proliferative inhibition to a specific drug combination of auranofin and AUY922. We profiled altered mechanistic responses from these agents in both reactive oxygen species and HSP90 pathways, as well as investigated PRKCI and lncRNA expression in ovarian cancer cell line models. Generation of dual multi-gene panels implicated in resistance or sensitivity to this drug combination was produced using RNA sequencing data and the validity of the resistant signature was examined using high-density RT-qPCR. Finally, data mining for the prevalence of these signatures in a large-scale clinical study alluded to the prevalence of resistant genes in ovarian tumor biology. Our results demonstrate that high-throughput viability screens paired with reliable in silico data can promote the discovery of effective, personalized therapeutic options for a currently untreatable disease.
Highlights
Drug repurposing circumvents the high costs and extended timeframes associated with drug discovery
Utilizing a robotic screening assay in a 384well format, we exposed ten epithelial ovarian cancer (EOC) cell lines to twelve different two-drug combination treatments using FDAapproved drugs not currently in use as EOC therapies (Supplementary Table 1)
Many of the single agent and drug combinations showed robust inhibition of cell viability across all lines, we were interested in drug combinations that demonstrate disparate phenotypes across EOC cell lines
Summary
Drug repurposing circumvents the high costs and extended timeframes associated with drug discovery. It is a cost-effective approach to identifying and prioritizing novel therapeutic combinations for low prevalence yet highly lethal diseases such as epithelial ovarian cancer (EOC), the deadliest of the gynecological diseases. Precision cancer medicine directed at distinct tumor vulnerabilities is imperative to make the vertical advancement in treatment in order to improve quality and www.oncotarget.com duration of life for EOC patients. There is a critical need to screen EOC tumors for specific genetic signatures to determine the most effective combinatorial treatment options on a case-by-case basis.
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