The EWS-FLI1 fusion oncoprotein occurring in 85% of Ewing sarcoma patients drives Ewing sarcomagenesis, rendering EWS-FLI1 as an ideal drug target. Although EWS-FLI1 downstream signaling and binding partners have been extensively studied, the mechanisms regulating EWS-FLI1 protein stability remain elusive. Here, we report that OTUD7A is a <i>bona fide</i> deubiquitinase that control EWS-FLI1 protein turnover in Ewing sarcoma. OTUD7A deubiquitinates and stabilizes EWS-FLI1 also depending on a specific degron sequence. Induced genetic depletion of OTUD7A in multiple Ewing sarcoma cell lines leads to reduced EWS-FLI1 protein abundance and impeded Ewing sarcoma growth <i>in vitro</i> and in mice. We performed an AI-based virtual drug screen using a 4 million small molecule compound library and identified a lead compound 7Ai as a potential OTUD7A catalytic inhibitor, which efficiently reduces EWS-FLI1 protein levels and retards Ewing sarcoma growth. Our study suggests the feasibility of therapeutically targeting OTUD7A as a new approach to treat Ewing sarcoma bearing EWS-FLI1 fusion.

Targeting the deubiquitinase OTUD7A in treating Ewing sarcoma

ACS Fall 2020 Virtual Meeting

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.