Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.
Pathology Center, Seegene Medical Foundation, Seoul 04805, Korea.
Cell Rep Med. 2023 Oct 17;4(10):101224. doi: 10.1016/j.xcrm.2023.101224. Epub 2023 Oct 4.
Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) is the standard care for muscle-invasive bladder cancers (MIBCs). However, the complete response rate to this modality remains relatively low, and current clinicopathologic and molecular classifications are inadequate to predict NAC response in patients with MIBC. Here, we demonstrate that dysregulation of the glutathione (GSH) pathway is fundamental for MIBC NAC resistance. Comprehensive analysis of the multicohort transcriptomes reveals that GSH metabolism and immune-response genes are enriched in NAC-resistant and NAC-sensitive MIBCs, respectively. A machine-learning-based tumor/stroma classifier is applied for high-throughput digitalized immunohistochemistry analysis, finding that GSH dynamics proteins, including glutaminase-1, are associated with NAC resistance. GSH dynamics is activated in cisplatin-resistant MIBC cells, and combination treatment with a GSH dynamics modulator and cisplatin significantly suppresses tumor growth in an orthotopic xenograft animal model. Collectively, these findings demonstrate the predictive and therapeutic values of GSH dynamics in determining the NAC response in MIBCs.
根治性膀胱切除术联合术前顺铂为基础的新辅助化疗（NAC）是肌层浸润性膀胱癌（MIBC）的标准治疗方法。然而，这种方法的完全缓解率仍然相对较低，目前的临床病理和分子分类不足以预测 MIBC 患者对 NAC 的反应。在这里，我们证明谷胱甘肽（GSH）途径的失调是 MIBC NAC 耐药的基础。对多队列转录组的综合分析表明，GSH 代谢和免疫反应基因分别在 NAC 耐药和 NAC 敏感的 MIBC 中富集。基于机器学习的肿瘤/基质分类器应用于高通量数字化免疫组化分析，发现包括谷氨酰胺酶-1 在内的 GSH 动力学蛋白与 NAC 耐药性相关。GSH 动力学在顺铂耐药性 MIBC 细胞中被激活，并且 GSH 动力学调节剂与顺铂的联合治疗显著抑制了原位异种移植动物模型中的肿瘤生长。总之，这些发现表明 GSH 动力学在确定 MIBC 中 NAC 反应方面具有预测和治疗价值。
