Abstract 4565: Bet bromodomain inhibitors affects replication & cell cycle progression

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Myc family of transcription factors contribute to pathogenesis in most cancers and their expression projects a poor prognosis. Genetic and pharmacological inhibition of Myc and several Myc targets leads to apoptosis and tumor regression. Recently, inhibitors of BET Bromodomain proteins (BETi) were shown to have anti-tumor properties and this has been attributed to Myc down-regulation. In this study, we show that two structurally distinct BETi affects replication and cell cycle progression at low concentrations where the transcriptome remains largely unaltered. At these concentrations, S-phase progression is hindered, as assessed by thymidine incorporation and flow cytometry analyses. However, in a cell-free system replication is not impaired suggesting that BETi-mediated block of replication is linked to effects on chromatin. Furthermore, at higher concentration of BET, S-phase entry of cells is completely abrogated. Ectopic expression of Myc fails to rescue these phenotypes, suggesting a novel function of BET bromodomain proteins in replication and cell cycle regulation. Citation Format: Somsundar Veppil Muralidharan, Joydeep Bhadury, Lydia Green, Lisa M. Nilsson, Kevin G. Mclure, Jonas A. Nilsson. Bet bromodomain inhibitors affects replication & cell cycle progression. [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 4565. doi:10.1158/1538-7445.AM2014-4565