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. The gene discussed is CUL3; the disease is Ewing sarcoma.