Abstract 486: BET protein inhibition by JQ1 blocks EWS-FLI1 activity in Ewing sarcoma

Abstract

Abstract Ewing sarcoma is the second most common bone cancer in children, with an estimated 5-year survival rate of 20% for metastatic cases. These tumors harbor the characteristic chromosomal translocation t(11;22)(q24;q12), which leads to expression of the oncogenic chimeric transcription factor, EWS-FLI1. EWS-FLI1 drives Ewing sarcoma tumorigenesis, and is an attractive therapeutic target because it is expressed exclusively in tumor cells. However, directly targeting EWS-FLI1 has proved difficult. Thus, despite advances in our understanding of EWS-FLI1 function, treatment options remain limited, and to date, no targeted therapeutics have been developed. In this study, we investigated the effects of the epigenetic modifier drug, JQ1, on Ewing sarcoma pathogenesis. JQ1 is a small molecule inhibitor of the BET family of bromodomain proteins, which bind to acetylated histones and transcription factors to regulate gene expression. JQ1 selectively inhibits these acetylation-dependent BET protein interactions. Recent studies reveal that JQ1 has potent anti-neoplastic activity against multiple cancers, with c-MYC downregulation being a key mechanism by which it induces cell death in several tumor types. Because Ewing sarcoma cells express high levels of c-MYC, we predicted that they would be sensitive to the cytotoxic effects of JQ1. Our results demonstrate that JQ1 indeed inhibits growth of Ewing sarcoma cells, but unexpectedly, it does not function through inhibition of c-MYC. Using multiple patient-derived Ewing sarcoma cell lines, we find that JQ1 induces apoptosis as measured by PARP cleavage. Preliminary data further indicate that JQ1 suppresses growth of Ewing sarcoma xenografts in vivo. Mechanistic studies and microarray analysis reveal that JQ1 inhibits EWS-FLI1 activity, with multiple targets of the oncogene being rapidly downregulated upon JQ1 treatment. Studies are currently underway to identify the specific BET family members required for EWS-FLI1 function, and to determine the mechanism by which they regulate EWS-FLI1 activity. Given the emergence of numerous JQ1-derivative compounds targeting specific BET proteins, it is hopeful that this class of compounds may ultimately be used as targeted therapies for the treatment of Ewing sarcoma. Citation Format: Krista L. Bledsoe, Aaron Stonestrom, Stephan Kadauke, Laura Quick, Robert Young, Gerd A. Blobel, Margaret M. Chou. BET protein inhibition by JQ1 blocks EWS-FLI1 activity in Ewing sarcoma. [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 486. doi:10.1158/1538-7445.AM2015-486