EWS-FLI1-regulated serine synthesis and exogenous serine are necessary for Ewing sarcoma cellular proliferation and tumor growth.

Abstract

Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma (ES), translation of basic discoveries into targeted therapies and significant clinical gains has remained elusive. Recent insights have revealed that the oncogenic transcription factor EWS-FLI1 can impact ES cellular metabolism, regulating expression of 3-phosphoglycerate dehydrogenase (PHGDH), the first enzyme in de novo serine synthesis. Here, we have examined the importance of serine metabolism in ES tumorigenesis and evaluated the therapeutic potential of targeting serine metabolism in preclinical models of ES. We show that PHGDH knockdown resulted in decreased ES cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of ES. Additionally, the PHGDH inhibitor NCT-503 caused a dose-dependent decrease in cellular proliferation. Moreover, we report a novel drug combination in which nicotinamide phosphoribosyltransferase (NAMPT) inhibition, which blocks production of the PHGDH substrate NAD+, synergized with NCT-503 to abolish ES cell proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited ES cell proliferation and tumorigenesis, indicating that ES cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for ES tumorigenesis, and that targeting metabolic dependencies should be further investigated as a potential therapeutic strategy for ES. In addition, the combination strategy presented herein may have broader clinical applications in other PHGDH-overexpressing cancers as well.

Authors

Issaq, Sameer H; Mendoza, Arnulfo; Kidner, Ria; Rosales, Tracy I; Duveau, Damien; Heske, Christine M; Rohde, Jason M; Boxer, Matthew B; Thomas, Craig; DeBerardinis, Ralph J; Helman, Lee J;

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