Abstract 3607: Loss-of-function screens using haploid KBM7 and HAP1 cells to identify mechanisms of anti-cancer drug resistance

Abstract

Abstract The lack of biomarkers to predict anti-cancer therapy response remains a major obstacle in the treatment of various cancers. This handicap not only affects novel targeted therapies. Also for classical chemotherapeutic drugs such as DNA cross-linking agents, topoisomerase inhibitors or microtubule-targeting compounds, which are all frequently used in the clinic, we do not understand well why some patients have a major benefit of the therapy whereas others do not. A decreased intracellular drug accumulation has been proposed as one potential mechanism, but the clinical relevance of known uptake and efflux mechanisms is still controversial for various chemotherapeutic drugs. To identify novel factors that may be relevant for the intracellular concentration of drugs, we carried out loss-of-function screens using haploid KBM7 and HAP1 cells. In particular, we used the PARP inhibitor olaparib, the topoisomerase I inhibitor topotecan, platinum drugs, and the microtubule-targeting compounds docetaxel and vinorelbine to select resistant clones. We will present results from these screens and their validation, including independent cell lines and TCGA data sets. Citation Format: Nora M. Gerhards, Charlotte Guyader, Vincent A. Blomen, Aslı Küçükosmanoğlu, Olaf van Tellingen, Daniel J. Vis, Lodewyk F. Wessels, Thijn R. Brummelkamp, Piet Borst, Sven Rottenberg. Loss-of-function screens using haploid KBM7 and HAP1 cells to identify mechanisms of anti-cancer drug resistance. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3607. doi:10.1158/1538-7445.AM2015-3607