Abstract 2358: Dissecting the cellular response to cisplatin from RNA transcription to translation

Abstract

Abstract Platinum-based antineoplastic drugs, such as cisplatin, are DNA damaging agents typically utilized in cancer treatment. In ovarian cancer, however, these drugs have a relatively low therapeutic index (which is a measure of clinical benefit over toxicity of these drugs), thus even a small change (reduction) in the cellular sensitivity to these chemotherapeutic agents leads to clinical treatment failure, also known as ‘drug resistance’. To increase the clinical efficacy of platinum-based antineoplastic drugs, we need to develop therapies that are less likely to result in drug resistance, or we need to modify the current therapies to prevent or reduce drug resistance. To gain mechanistic insights into the process of drug resistance that may help us to develop new or modified therapies that are less prone to clinical drug resistance, we have focused our studies on the comprehensive analysis of two still poorly studied cisplatin-associated processes at genome-wide scale: the processes of RNA nascent transcription and RNA translation. In particular, we investigate by global run-on combined with next-generation sequencing (GRO-seq) how cisplatin-sensitive A2780 ovarian cancer cells and its cisplatin-resistance derivative, A2780cis cells, respond to acute cisplatin treatment at the level of the nascent transcriptome. We also investigate, in this case by ribosome profiling, how the same cells respond to acute cisplatin treatment at the level of the ribosome-associated transcriptome (also known as translatome). These two massive analyses, complemented with conventional profiling of steady-state RNA (profiled by RNA-seq) provide the first multidimensional analysis of the actions induced by any chemotherapeutic agent at the level of the three basic states of the transcriptome (nascent RNA, steady-state RNA, and translated RNA). Interestingly, this analysis reveals an unexpected large fraction of uncoupled events between these three transcriptomic states, which challenges the conventional one-dimensional approach based exclusively on RNA-seq for the study of drug resistance. Note: This abstract was not presented at the meeting. Citation Format: Carlos Mackintosh, Sergiy Konovalov, Ivan Garcia-Bassets. Dissecting the cellular response to cisplatin from RNA transcription to translation. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2358. doi:10.1158/1538-7445.AM2014-2358