胰腺导管腺癌 (PDAC) 细胞使用谷氨酰胺 (Gln) 来支持增殖和氧化还原平衡。早期尝试使用谷氨酰胺酶抑制剂抑制谷氨酰胺代谢，导致快速代谢重编程和治疗耐药。在这里，我们证明用 Gln 拮抗剂 6-diazo-5-oxo-L-norleucine (DON) 处理 PDAC 细胞会导致体外代谢危机。此外，我们在使用sirpiglenastat (DRP-104)的几个体内模型中观察到肿瘤生长显着减少，sirpiglenastat (DRP-104)是DON的前药版本，旨在规避与DON相关的毒性。我们发现细胞外信号调节激酶（ERK）信号传导作为一种补偿机制而增加。 DRP-104 和曲美替尼的联合治疗导致 PDAC 同基因模型的生存率显着增加。这些概念验证研究表明，广泛针对 Gln 代谢可以为 PDAC 提供治疗途径。与 ERK 信号通路抑制剂的组合可以进一步改善治疗结果。© 2023。作者。

Pancreatic ductal adenocarcinoma (PDAC) cells use glutamine (Gln) to support proliferation and redox balance. Early attempts to inhibit Gln metabolism using glutaminase inhibitors resulted in rapid metabolic reprogramming and therapeutic resistance. Here, we demonstrated that treating PDAC cells with a Gln antagonist, 6-diazo-5-oxo-L-norleucine (DON), led to a metabolic crisis in vitro. In addition, we observed a profound decrease in tumor growth in several in vivo models using sirpiglenastat (DRP-104), a pro-drug version of DON that was designed to circumvent DON-associated toxicity. We found that extracellular signal-regulated kinase (ERK) signaling is increased as a compensatory mechanism. Combinatorial treatment with DRP-104 and trametinib led to a significant increase in survival in a syngeneic model of PDAC. These proof-of-concept studies suggested that broadly targeting Gln metabolism could provide a therapeutic avenue for PDAC. The combination with an ERK signaling pathway inhibitor could further improve the therapeutic outcome.© 2023. The Author(s).