Abstract
Abstract Ovarian cancer is the most lethal gynecologic malignancy. The treatment of platinum resistance disease remains an urgent and unmet clinical need. Identification of bromodomain inhibitors to disrupt “reading” of aberrant protein acetylation marks in cancer, leading to down-regulation of lineage-specific oncogenes is an exciting development in epigenetic drug therapy. The oncogenic transcription factor c-MYC (MYC) is amplified in approximately 30-40% of high grade serous ovarian tumors and may be epigenetically deregulated via a “super enhancer” on chromosome 8q24. JQ1, an inhibitor of bromodomain binding, down-regulates MYC expression in MYC-amplified tumors. However, this mechanism appears to be tissue-specific and has not been tested as a method for chemosensitization in ovarian cancer. We hypothesized that JQ1 could be used to enhance cisplatin cytotoxicity in ovarian cancer cells, in part by repression of MYC. Ovarian cancer cell lines were selected after in silico evaluation of publically available, annotated cell line collections. Cell lines with relatively low expression of MYC (IGROV-1 and SKOV3) and relatively high expression, A2780 parental [A2780PAR] and isogenic cisplatin-resistant A2780CP20 cells) were treated with 0.1% DMSO, JQ1, cisplatin or the combination of drugs. Sulforhodamine B (SRB) and clonogenic assays were used to assess effects on cell viability. Apoptosis was evaluated by Western Blot detection of cleaved PARP. Expression of MYC was measured by QPCR and Western Blot. JQ1 reduced cell viability and clonogenicity at sub-micromolar concentrations in the ovarian cancer cell lines examined. Furthermore, JQ1 treatment sensitized ovarian cancer cells, including the resistant A2780CP20, to the growth inhibitory and pro-apoptotic effects of cisplatin. However, the cytotoxic effects of JQ1 were not directly correlated with down-regulation of MYC. First, A2780PAR and A2780CP20 cells expressed the highest basal levels of MYC in our panel, but were not the most sensitive to JQ1-induced anti-tumor effects. Second, JQ1 markedly inhibited MYC expression in A2780PAR, but not A2780CP20 cells, despite relatively similar reduction in growth inhibition by JQ1 alone and combined with cisplatin in these cell lines. Taken together, these novel findings suggest that JQ1 could be used to sensitize ovarian cancer cells to platinum-based therapy. Identifying oncogenic targets of JQ1 other than MYC in ovarian cancer is a priority for further development of bromodomain inhibitors in ovarian cancer. Citation Format: Dineo Khabele, Andrew J. Wilson, Jeanette Saskowski, Scott W. Hiebert. The bromodomain inhibitor JQ1 enhances cisplatin-mediated cytotoxicity in ovarian cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr B52.
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