Abstract IA04: Targeting the expression of EWS-FLI1

Post-translational modifications (PTMs) of transcription factors represent potential therapeutic targets for a variety of diseases, including cancer. In the majority of cases of the bone and soft tissue tumor Ewing sarcoma (ES), a chromosomal translocation, t(11:22), results in expression of the fusion transcription factor EWS-FLI1. Few PTMs of EWS-FLI1 have been identified. Using functional genetic methods and mass spectrometry analysis, we have identified a phosphorylated serine residue in the FLI1 domain of EWS-FLI1 that regulates the stability of the EWS-FLI1 oncoprotein. Loss of phosphorylation of this serine residue triggers ubiquitination and proteasomal degradation of EWS-FLI1, and apoptotic cell death. Xenograft studies suggest this post-translational modification of EWS-FLI1 can be targeted in vivo and that this inhibits ES tumor growth. Citation Format: Nirmalya Sen, Katelyn Ludwig, Guillermo O. Rangel-Rivera, Suntae Kim, Konrad Huppi, Lisa Jenkins, Jennifer E. Dwyer, Shelley Hoover, Lee Helman, Mark Simpson, Arnulfo Mendoza, Amanda B. Hummon, Natasha J. Caplen. Targeting the expression of EWS-FLI1 [abstract]. In: Proceedings of the AACR Conference on Advances in Sarcomas: From Basic Science to Clinical Translation; May 16-19, 2017; Philadelphia, PA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(2_Suppl):Abstract nr IA04.