LAUSR

Simple Summary Ewing sarcoma is a malignant pediatric bone cancer currently lacking targeted therapy. In the US there are ~200 patients diagnosed each year and relapse is associated with resistance to the standard-of-care chemotherapy. Thus, it remains an urgent unmet medical need to develop effective new cures for Ewing sarcoma. It is well-characterized that Ewing sarcoma is largely driven by unique gene fusions, with EWSR1-FLI1 being the most prevalent. In this review, we summarize up-to-date regulatory mechanisms for the onco-fusion protein EWSR1-FLI1 in Ewing sarcoma, including both post-transcriptional and post-translational modifications, to reveal knowledge gaps and propose potential new therapeutic directions. Abstract Ewing sarcoma is the second most common bone tumor in childhood and adolescence. Currently, first-line therapy includes multidrug chemotherapy with surgery and/or radiation. Although most patients initially respond to chemotherapy, recurrent tumors become treatment refractory. Pathologically, Ewing sarcoma consists of small round basophilic cells with prominent nuclei marked by expression of surface protein CD99. Genetically, Ewing sarcoma is driven by a fusion oncoprotein that results from one of a small number of chromosomal translocations composed of a FET gene and a gene encoding an ETS family transcription factor, with ~85% of tumors expressing the EWSR1::FLI1 fusion. EWSR1::FLI1 regulates transcription, splicing, genome instability and other cellular functions. Although a tumor-specific target, EWSR1::FLI1-targeted therapy has yet to be developed, largely due to insufficient understanding of EWSR1::FLI1 upstream and downstream signaling, and the challenges in targeting transcription factors with small molecules. In this review, we summarize the contemporary molecular understanding of Ewing sarcoma, and the post-transcriptional and post-translational regulatory mechanisms that control EWSR1::FLI1 function.