Druggable upregulated proteins in EWS-FLI-driven Ewing sarcoma as emerging new therapeutic targets

Ewing sarcoma (ES) is a highly aggressive soft tissue tumor that primarily affects the long bones of children and young adults. It is distinguished by a characteristic chromosomal translocation between the Ewing sarcoma breakpoint region 1 (EWS) gene and the erythroblast transformation-specific (ETS) family of genes, most commonly resulting in the EWS-friend leukemia integration 1 (EWS-FLI1) fusion gene. This translocation is observed in approximately 80%-85% of ES cases. This fusion gene encodes a non-physiological chimeric fusion protein that plays a central role in tumorigenesis by interacting with numerous partner proteins. Several studies have demonstrated the tumorigenic potential of the EWS-FLI1 protein when transfected into non-cancer cell lines. However, targeting EWS-FLI1 directly remains a significant challenge, as no drug to date has been reported to bind to and inhibit its activity effectively. An alternative therapeutic strategy involves targeting key overexpressed protein complexes implicated in ES tumorigenesis, many of which may be downstream interacting partners of EWS-FLI1. This review explores emerging protein targets as potential therapeutic avenues in ES treatment.