Together, these data further support a physiological role of SPOPCUL3 in targeting EWS–FLI1 for degradation and suggest that Ewing sarcoma tumors may inactivate SPOP‐mediated EWS–FLI1 degradation through CUL3 mutations to promote Ewing sarcoma growth. This evidence concerns the gene FLI1 and Ewing sarcoma.