谷氨酰胺是快速增殖的癌细胞生长和存活的条件必需氨基酸。许多癌症都对谷氨酰胺上瘾，因此临床上已经探索了针对谷氨酰胺代谢的治疗方法。谷氨酰胺催化酶在原发性和转移性头颈鳞状细胞癌 (HNSCC) 中高表达。然而，这种侵袭性癌症类型中谷氨酰胺相关途径的性质尚未阐明。在这里，我们探索了广泛的谷氨酰胺拮抗剂 DRP-104（sirpiglenastat）在 HNSCC 肿瘤中的治疗潜力，旨在揭示该疾病中谷氨酰胺依赖性途径。我们观察到 sirpiglenastat 在 HPV 和 HPV HNSCC 异种移植物中具有有效的抗肿瘤作用。我们进行了全基因组 CRISPR 筛选和代谢组学分析，以确定对谷氨酰胺代谢阻断的敏感性和抗性机制。这些方法表明，谷氨酰胺代谢阻断会通过自噬营养感应途径导致多不饱和脂肪酸（PUFA）快速积累。最后，我们的分析表明，GPX4 介导保护 HNSCC 细胞免于积累有毒脂质过氧化物；因此，谷氨酰胺阻断使 HNSCC 细胞对 GPX4 抑制后的铁死亡细胞敏感。这些发现证明了西匹格列他在 HNSCC 中的治疗潜力，并在谷氨酰胺代谢和铁死亡之间建立了一种新的联系，这可以独特地转化为靶向谷氨酰胺-铁死亡联合疗法。版权所有 © 2024。由 Elsevier B.V. 出版。

Glutamine is a conditionally essential amino acid for the growth and survival of rapidly proliferating cancer cells. Many cancers are addicted to glutamine, and as a result, targeting glutamine metabolism has been explored clinically as a therapeutic approach. Glutamine-catalyzing enzymes are highly expressed in primary and metastatic head and neck squamous cell carcinoma (HNSCC). However, the nature of the glutamine-associated pathways in this aggressive cancer type has not been elucidated. Here, we explored the therapeutic potential of a broad glutamine antagonist, DRP-104 (sirpiglenastat), in HNSCC tumors and aimed at shedding light on glutamine-dependent pathways in this disease. We observed a potent antitumoral effect of sirpiglenastat in HPV- and HPV+ HNSCC xenografts. We conducted a whole-genome CRISPR screen and metabolomics analyses to identify mechanisms of sensitivity and resistance to glutamine metabolism blockade. These approaches revealed that glutamine metabolism blockade results in the rapid buildup of polyunsaturated fatty acids (PUFAs) via autophagy nutrient-sensing pathways. Finally, our analysis demonstrated that GPX4 mediates the protection of HNSCC cells from accumulating toxic lipid peroxides; hence, glutamine blockade sensitizes HNSCC cells to ferroptosis cell death upon GPX4 inhibition. These findings demonstrate the therapeutic potential of sirpiglenastat in HNSCC and establish a novel link between glutamine metabolism and ferroptosis, which may be uniquely translated into targeted glutamine-ferroptosis combination therapies.Copyright © 2024. Published by Elsevier B.V.