Abstract LB-099: BET bromodomain proteins are essential for the oncogenic EWS-fusion driven Ewing Sarcoma

Abstract Ewing sarcoma (EWS) is a lethal pediatric small, round, blue cell tumor defined by the characteristic fusion between EWSR1 and a member of the ETS family transcription factor, mostly FLI1 and ERG. Bromodomain and extra-terminal domain (BET) proteins play an essential role in transcription as an epigenetic reader of acetylated histones and transcription factors, and recent studies of inhibitors against these proteins have demonstrated therapeutic potential in various cancers. In this study, we investigated the importance of BET proteins BRD2, BRD3, and BRD4 in EWS-fusion driven transcription program required for maintenance and progression of EWS. Similar to EWS-FLI1 and EWS-ERG, knock-down of BET proteins severely impaired the proliferation and invasion of EWS cells. Gene expression profiling by RNA-Seq showed a common set of genes altered in EWS-FLI1 and BRD2/3/4 knockdown cells implicating a direct role of BET proteins in the transcriptional regulation of EWS-fusion targets. Importantly, BET inhibitor, JQ1, induces apoptosis in EWS cells through an MYC-independent mechanism, and without affecting the EWS-fusion levels. Rather, evidence suggested that BRD4 exists in a complex with EWS-ETS fusion proteins and that its inhibition abrogates the fusion transcriptional program. In vivo, JQ1 inhibited the metastases in chicken CAM model of EWS as well as displayed anti-tumor and anti-metastatic activity in mouse xenograft models of EWS. Together, these results indicate that BET proteins, especially BRD4 interacts with EWS-ETS fusion proteins and this interaction is necessary for the EWS-fusion mediated oncogenesis. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating metastatic Ewing sarcoma patients. Citation Format: Paradesi N. Gollavilli, Aishwarya Pawar, Kari Wilder-Romans, Carl Engelke, Vijaya L. Dommeti, Pranathi M. Krishnamurthy, Archana Nallasivam, Ingrid A. Apel, Tianlei Xu, Zhaohui S. Qin, Felix Y. Feng, Irfan A. Asangani. BET bromodomain proteins are essential for the oncogenic EWS-fusion driven Ewing Sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-099. doi:10.1158/1538-7445.AM2017-LB-099