The efficacy of ionizing radiation (IR) for head and neck cancer squamous cell carcinoma (HNSCC) is limited by poorly understood mechanisms of adaptive radioresistance. Elevated glutaminase gene expression is linked to significantly reduced survival (p < 0.03). The glutaminase inhibitor, telaglenastat (CB-839), has been tested in Phase I/II cancer trials and is well tolerated by patients. This study investigated if telaglenastat enhances the cellular response to IR in HNSCC models. Using three human HNSCC cell lines and two xenograft mouse models, we examined telaglenastat's effects on radiation sensitivity. IR and telaglenastat combinatorial treatment reduced cell survival (p ≤ 0.05), spheroid size (p ≤ 0.0001) and tumor growth in CAL-27 xenograft bearing mice relative to vehicle (p ≤ 0.01), telaglenastat (p ≤ 0.05) or IR (p ≤ 0.01) monotherapy. Telaglenastat significantly reduced the Oxygen Consumption Rate/Extracellular Acidification Rate ratio in CAL-27 and HN5 cells in the presence of glucose and glutamine (p ≤ 0.0001). Telaglenastat increased oxidative stress and DNA damage in irradiated CAL-27 cells. These data suggest that combination treatment with IR and telaglenastat leads to an enhanced anti-tumor response. This pre-clinical data, combined with the established safety of telaglenastat justifies further investigation for the combination in HNSCC patients.

电离辐射 (IR) 对头颈癌鳞状细胞癌 (HNSCC) 的疗效受限于对适应性放射抗性机制知之甚少。谷氨酰胺酶基因表达升高与存活率显着降低有关（p < 0.03）。谷氨酰胺酶抑制剂 telaglenastat (CB-839) 已在 I/II 期癌症试验中进行了测试，患者耐受性良好。本研究调查了 telaglenastat 是否增强了 HNSCC 模型中对 IR 的细胞反应。我们使用三种人类 HNSCC 细胞系和两种异种移植小鼠模型，研究了 telaglenastat 对辐射敏感性的影响。相对于载体 (p ≤ 0.01)、telaglenastat (p ≤ 0.05) 或 IR (p ≤ 0。01) 单一疗法。在葡萄糖和谷氨酰胺存在的情况下，Telaglenastat 显着降低了 CAL-27 和 HN5 细胞的耗氧率/细胞外酸化率比值 (p ≤ 0.0001)。Telaglenastat 增加了受照射的 CAL-27 细胞中的氧化应激和 DNA 损伤。这些数据表明，IR 和 telaglenast 联合治疗可增强抗肿瘤反应。这一临床前数据，结合 telaglenastat 的既定安全性，证明对 HNSCC 患者的组合进行进一步研究是合理的。这些数据表明，IR 和 telaglenast 联合治疗可增强抗肿瘤反应。这一临床前数据，结合 telaglenastat 的既定安全性，证明对 HNSCC 患者的组合进行进一步研究是合理的。这些数据表明，IR 和 telaglenast 联合治疗可增强抗肿瘤反应。这一临床前数据，结合 telaglenastat 的既定安全性，证明对 HNSCC 患者的组合进行进一步研究是合理的。