One-Carbon Metabolism Inhibition Depletes Purines and Results in Profound and Prolonged Ewing Sarcoma Growth Suppression.
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UNLABELLED: Ewing sarcoma is the second most common primary bone malignancy in adolescents and young adults. Patients who present with localized disease have experienced a steadily improving survival rate over the years, whereas those who present with metastatic disease have the same dismal prognosis as 30 years ago, with long-term survival rates of less than 20%, despite maximal intensification of chemotherapy. Thus, novel treatment approaches are a significant unmet clinical need. Targeting metabolic differences between Ewing sarcoma and normal cells offers a promising approach to improve outcomes for these patients. One-carbon metabolism utilizes serine and folate to generate glycine and tetrahydrofolate-bound one-carbon units required for de novo nucleotide biosynthesis. Elevated expression of several one-carbon metabolism genes is significantly associated with reduced survival in patients with Ewing sarcoma. We show that both genetic inhibition and pharmacologic inhibition of a key enzyme of the mitochondrial arm of the one-carbon metabolic pathway, serine hydroxymethyltransferase 2, lead to substantial inhibition of Ewing sarcoma cell proliferation and colony-forming ability and that this effect is primarily caused by depletion of glycine and one-carbon units required for the synthesis of purine nucleotides. Inhibition of one-carbon metabolism at a different node, using the clinically relevant dihydrofolate reductase inhibitor pralatrexate, similarly yields profound growth inhibition, with depletion of thymidylate and purine nucleotides. Genetic depletion of serine hydroxymethyltransferase 2 dramatically impairs tumor growth in a xenograft model of Ewing sarcoma. Together, these data establish dependence on one-carbon metabolism as a novel and targetable vulnerability of Ewing sarcoma cells, which can be exploited for therapy. SIGNIFICANCE: Using both genetic and pharmacologic approaches, this study identifies Ewing sarcoma's dependence on one-carbon metabolism as a targetable vulnerability that can be effectively harnessed for therapy.