We sought to elucidate the resistance factors to PARP inhibitor therapy in Ewing sarcoma and identify a rational drug combination capable of rescuing PARP inhibitor activity.
The combination of these molecules with PARP inhibitors showed striking synergy in cell viability and DNA damage assays in vitro and in multiple models of Ewing sarcoma, including a PDX, in vivo without hematopoietic toxicity.
EWS-FLI1-mediated SLFN11 expression is responsible for high sensitivity of Ewing sarcoma to camptothecin and combinations of PARP inhibitors with temozolomide.