SLFN11 Loss-Induced Chemoresistance is Associated with Overexpression of Glycerophospholipid Biosynthesis in Ewing Sarcoma

Ewing sarcoma (EWS) is an aggressive cancer in adolescents and young adults with frequent relapse rates and poor outcomes in recurrent or metastatic cases. Schlafen family member 11 ( SLFN11 ) gene is associated with the sensitivity to DNA-damaging agents (DDAs). The knockout of SLFN11 is associated with acquired chemoresistance in both cell lines and preclinical models. Here, we aimed to elucidate the metabolic underpinnings of SLFN11 -loss associated chemoresistance in patient derived cell lines of EWS. Our integrated transcriptomic and metabolomic analyses revealed downregulation of mitochondrial glycerol-3-phosphate dehydrogenase 2 ( GPD2 ) gene, which was accompanied by the upregulation of glycerophospholipid (GPL) biosynthesis pathway. Further, therapeutic targeting of lipid synthesis with the glycerol-3-phosphate acyltransferase 1 (GPAT1) inhibitor (FSG67) enhanced the efficacy of the DDA (SN-38) in SLFN11 ^−/− cells. These findings indicate that SLFN11 loss-mediated chemoresistance can be targeted by blocking GPL biosynthesis in addition to DDA administration.