在胰腺导管腺癌 (PDAC) 中，谷氨酰胺是一种关键营养素，可驱动支持肿瘤生长的各种代谢和生物合成过程。在这里，我们阐明了 6-重氮-5-氧代-L-正亮氨酸 (DON)（一种广泛抑制谷氨酰胺代谢的谷氨酰胺拮抗剂）如何阻止 PDAC 肿瘤生长和转移。我们发现 DON 通过抑制天冬酰胺合成酶 (ASNS) 显着减少天冬酰胺的产生，并且天冬酰胺可以挽救 DON 的作用。作为一种代谢适应，PDAC 细胞响应 DON 上调 ASNS 表达，我们发现 ASNS 水平与 DON 功效呈负相关。我们还表明，L-天冬酰胺酶 (ASNase) 与 DON 协同作用，影响 PDAC 细胞的活力，并且 DON 和 ASNase 联合治疗对转移有显着影响。这些结果揭示了驱动谷氨酰胺拟态效应的机制，并指出了共靶向适应性反应在控制 PDAC 进展方面的效用。© 2023。作者获得 Springer Nature America, Inc. 的独家许可。

In pancreatic ductal adenocarcinoma (PDAC), glutamine is a critical nutrient that drives a wide array of metabolic and biosynthetic processes that support tumor growth. Here, we elucidate how 6-diazo-5-oxo-L-norleucine (DON), a glutamine antagonist that broadly inhibits glutamine metabolism, blocks PDAC tumor growth and metastasis. We find that DON significantly reduces asparagine production by inhibiting asparagine synthetase (ASNS), and that the effects of DON are rescued by asparagine. As a metabolic adaptation, PDAC cells upregulate ASNS expression in response to DON, and we show that ASNS levels are inversely correlated with DON efficacy. We also show that L-asparaginase (ASNase) synergizes with DON to affect the viability of PDAC cells, and that DON and ASNase combination therapy has a significant impact on metastasis. These results shed light on the mechanisms that drive the effects of glutamine mimicry and point to the utility of cotargeting adaptive responses to control PDAC progression.© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.