The kinase inhibitor GNF-7 is synthetically lethal in topoisomerase 1 deficient Ewing Sarcoma

Relapsed Ewing sarcoma is treated with TOP1 inhibitors. Our study confirmed prior studies showing that downregulation of TOP1 is a mechanism of resistance to camptothecin. We then screened a large library of clinically relevant compounds and found that TOP1-deficient Ewing sarcoma cells are more sensitive to the kinase inhibitor GNF-7. RNA-seq results reveal that GNF-7 modulates EWS/FLI1 gene signatures in both TOP1 wild type and TOP1-deficient cells. Overall design: RNA-seq was performed for gene expression profiling analysis in EW8 wildtype (WT) and EW8 TOP1 (TOP1 KD) knockdown cells treated with 40nM GNF-7 for 0h, 4h, 8h, 16h, 24h, 48h, and 72h.