Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer
YongHwan Kim, Hyein Ju, Seung-Yeon Yoo, Jinahn Jeong, Jinbeom Heo, Seungun Lee, Ja-Min Park, Sun Young Yoon, Se Un Jeong, Jin‐Young Lee, Jin‐Young Lee, HongDuck Yun, Chae‐Min Ryu, Jinah Lee, Jinah Lee, Yun Ji Nam, Hyungu Kwon, Jaekyoung Son, Gowun Jeong, Ji‐Hye Oh, Chang Ohk Sung, Eui Man Jeong, Jaehoon An, Sungho Won, Bumsik Hong, Jae‐Lyun Lee, Jae‐Lyun Lee, Yong Mee Cho, Dong‐Myung Shin
Abstract
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.