Abstract POSTER-TECH-1111: High-throughput drug sensitivity and resistance testing of ovarian cancer cell lines provides useful strategy for assessing drug repositioning and therapeutic possibilities of emerging drugs

Abstract

Abstract As almost all therapeutic approaches for ovarian cancer (OC) are organ-based therapies that have been tested in large-scale clinical studies, no precision medicine approach to OC currently exists. There is an urgent need to develop a better understanding of the drug responsiveness in OC, particularly in the clear cell and mucinous subtypes, which tend to be resistant to the commonly used platinum-based regimens. This would help to improve survival and facilitate precision medicine therapy approaches. In order to discover previously unsuspected anti-cancer effects of approved and emerging drugs, we applied Drug Sensitivity and Resistance Testing (DSRT) technology (Pemovska et al., Cancer Discovery, 2013) to determine detailed dose-response effects of 306 drugs in 29 established OC cell lines (12 clear cell, 6 mucinous, 1 endometrioid, and 10 serous and other OC cell lines). The panel covered 137 approved drugs as well as emerging, investigational and pre-clinical oncology compounds such as kinase and non-kinase inhibitors. All drugs were tested at 5 different concentrations, covering a 10,000-fold concentration range by using Labcyte nano-dispensing technology, in order to generate detailed dose-response curves for each drug in each cell line. The area under the curve was estimated from the dose-response curve to obtain the drug sensitivity score. Bioinformatic processing of the drug response data from OC cell lines resulted in several key observations. First, the clusters did not depend on the histological origin of the OC cell lines but were clustered according to drug categories. Second, our result showed that many emerging or non-approved drugs were sensitive in subgroups of OC cell lines. For example, MEK inhibitors and mTOR inhibitors show high sensitivity in many OC cell lines. They can be candidates for drug repositioning. Third, we confirmed reproducibility of our findings. In summary, as per the data from direct testing of drug efficacy, several emerging anti-cancer drugs show potential responses in subsets of OC cell lines. DSRT technology provides a powerful strategy for assessing drug response in OC cell models, and it could also help asses drug responses in patient-derived ex vivo model systems of OC. Analysis of correlations of DSRT data with genomic data of the cell lines is underway and will yield new translational and pharmacogenomic opportunities for treating OC. Citation Format: Akira Hirasawa, Astrid Murumägi, Mariliina Arjama, Bhagwan Yadav, John Patrick Mpindi, Krister Wennerberg, Tero Aittokallio, Daisuke Aoki, Olli Kallioniemi. High-throughput drug sensitivity and resistance testing of ovarian cancer cell lines provides useful strategy for assessing drug repositioning and therapeutic possibilities of emerging drugs [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr POSTER-TECH-1111.