Mesenchymal Phenotype Predisposes Lung Cancer Cells to Impaired Proliferation and Redox Stress in Response to Glutaminase Inhibition

Recent work has highlighted glutaminase (GLS) as a key player in cancer cell metabolism, providing glutamine-derived carbon and nitrogen to pathways that support proliferation. There is significant interest in targeting GLS for cancer therapy, although the gene is not known to be mutated or amplified in tumors. As a result, identification of tractable markers that predict GLS dependence is needed for translation of GLS inhibitors to the clinic. Herein we validate a small molecule inhibitor of GLS and show that non-small cell lung cancer cells marked by low E-cadherin and high vimentin expression, hallmarks of a mesenchymal phenotype, are particularly sensitive to inhibition of the enzyme. Furthermore, lung cancer cells induced to undergo epithelial to mesenchymal transition (EMT) acquire sensitivity to the GLS inhibitor. Metabolic studies suggest that the mesenchymal cells have a reduced capacity for oxidative phosphorylation and increased susceptibility to oxidative stress, rendering them unable to cope with the perturbations induced by GLS inhibition. These findings elucidate selective metabolic dependencies of mesenchymal lung cancer cells and suggest novel pathways as potential targets in this aggressive cancer type.

近期研究凸显了谷氨酰胺酶（glutaminase, GLS）作为癌细胞代谢关键调控因子的重要作用，其可为支持肿瘤细胞增殖的通路提供谷氨酰胺来源的碳源与氮源。尽管该基因在肿瘤中尚未被检测到突变或扩增，但靶向GLS以开发癌症治疗手段已受到广泛关注。因此，亟需识别可预测GLS依赖性的可行标志物，以推动GLS抑制剂向临床应用的转化。本研究验证了一款GLS小分子抑制剂，并证实以低E-钙粘蛋白（E-cadherin）、高波形蛋白（vimentin）表达为间充质表型特征的非小细胞肺癌细胞，对该酶抑制剂尤为敏感。此外，被诱导发生上皮间质转化（epithelial to mesenchymal transition, EMT）的肺癌细胞也会获得对GLS抑制剂的敏感性。代谢研究显示，间充质型肺癌细胞的氧化磷酸化能力降低，且对氧化应激的易感性增强，使其无法应对GLS抑制所引发的代谢扰动。上述研究结果阐明了间充质型肺癌细胞的选择性代谢依赖性，并为这类侵袭性癌症亚型提出了潜在的新型治疗靶点通路。