Despite a growing body of knowledge about the genomic landscape of Ewing sarcoma, 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 Ewing sarcoma 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 Ewing sarcoma tumorigenesis and evaluated the therapeutic potential of targeting serine metabolism in preclinical models of Ewing sarcoma. We show that PHGDH knockdown resulted in decreased Ewing sarcoma cell proliferation, especially under serine limitation, and significantly inhibited xenograft tumorigenesis in preclinical orthotopic models of Ewing sarcoma. In addition, 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 Ewing sarcoma cell proliferation and tumor growth. Furthermore, we show that serine deprivation inhibited Ewing sarcoma cell proliferation and tumorigenesis, indicating that Ewing sarcoma cells depend on exogenous serine in addition to de novo serine synthesis. Our findings suggest that serine metabolism is critical for Ewing sarcoma tumorigenesis, and that targeting metabolic dependencies should be further investigated as a potential therapeutic strategy for Ewing sarcoma. In addition, the combination strategy presented herein may have broader clinical applications in other PHGDH-overexpressing cancers as well.

中文翻译：

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EWS-FLI1 调节的丝氨酸合成和外源性丝氨酸是尤文肉瘤细胞增殖和肿瘤生长所必需的

尽管对尤文肉瘤的基因组景观有越来越多的了解，但将基本发现转化为靶向治疗和显着的临床成果仍然难以捉摸。最近的见解表明，致癌转录因子 EWS-FLI1 可以影响尤文肉瘤细胞代谢，调节 3-磷酸甘油酸脱氢酶 (PHGDH) 的表达，这是从头合成丝氨酸的第一种酶。在这里，我们研究了丝氨酸代谢在尤文肉瘤肿瘤发生中的重要性，并评估了在尤文肉瘤的临床前模型中靶向丝氨酸代谢的治疗潜力。我们表明，PHGDH 敲低导致尤文肉瘤细胞增殖减少，尤其是在丝氨酸限制下，并显着抑制尤文肉瘤临床前原位模型中的异种移植肿瘤发生。此外，PHGDH 抑制剂 NCT-503 引起细胞增殖的剂量依赖性降低。此外，我们报告了一种新的药物组合，其中烟酰胺磷酸核糖基转移酶 (NAMPT) 抑制可阻断 PHGDH 底物 NAD+ 的产生，与 NCT-503 协同作用以消除尤文肉瘤细胞增殖和肿瘤生长。此外，我们表明丝氨酸剥夺抑制了尤文肉瘤细胞增殖和肿瘤发生，表明除了从头合成丝氨酸外，尤文肉瘤细胞还依赖于外源丝氨酸。我们的研究结果表明，丝氨酸代谢对于尤文肉瘤的肿瘤发生至关重要，应该进一步研究靶向代谢依赖性作为尤文肉瘤的潜在治疗策略。此外，