Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer

Sep 24, 2026

Uploaded by Mimi

Radical cystectomy with preoperative cisplatin-based neoadjuvant chemotherapy (NAC) remains standard for muscle-invasive bladder cancer, yet complete responses are relatively uncommon and existing clinicopathologic and molecular classifications poorly predict NAC outcomes. The study integrates multicohort transcriptomic and clinical data, along with digital pathology, live-cell imaging, and in vitro/in vivo modeling, to show that glutathione (GSH) pathway dysregulation underpins NAC resistance.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages26

Reading Time1 h 6 min

AccessFree to download

Summary

Introduction

Results (implied by study aims)

Multicohort transcriptomic and clinical analysis

Discovery and validation of GSH dynamic features

Role of glutaminase-1 in regulating GSH dynamics

Therapeutic targeting to resensitize chemoresistant tumors

Article Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer Authors YongHwan Kim, Hyein Ju, Seung-Yeon Yoo, ..., Jae Lyun Lee, Yong Mee Cho, Dong-Myung Shin Correspondence [jaelyun@amc.seoul.kr](jaelyun@amc.seoul.kr) (J.L.L.), [yongcho@amc.seoul.kr](yongcho@amc.seoul.kr) (Y.M.C.), [d0shin03@amc.seoul.kr](d0shin03@amc.seoul.kr) (D.-M.S.) In brief Kim et al. integrate multicohort transcriptomic and clinical data analysis of MIBC patients, digital pathology, livecell imaging, and in vitro and in vivo modeling. They highlight the importance of glutathione dynamics as a predictive biomarker for MIBC’s response topreoperative cisplatin-based neoadjuvant chemotherapy and a potential therapeutic target for chemoresistant MIBCs. d MIBC multicohort analysis of molecular and clinical data for NAC responsiveness d Discovery and validation of GSH dynamic features for predicting responses to NAC d Glutaminase-1 is a key factor regulating GSH dynamics inhuman MIBC cells d Modulation of GSH dynamics resensitizes chemoresistant MIBCs Kim et al., 2023, Cell Reports Medicine 4, 101224 October 17, 2023 ª 2023 The Author(s) . [https://doi.org/10.1016/j.xcrm.2023.101224](https://doi.org/10.1016/j.xcrm.2023.101224) ll ll OPEN ACCESS Article Glutathione dynamics is a potential predictive and therapeutic trait for neoadjuvant chemotherapy response in bladder cancer YongHwan Kim,1,13 Hyein Ju,1,13 Seung-Yeon Yoo,2,13 Jinahn Jeong,3 Jinbeom Heo,1 Seungun Lee,1 Ja-Min Park,3 Sun Young Yoon,3 Se Un Jeong,4 Jinyoung Lee,5 HongDuck Yun,1 Chae-Min Ryu,6 Jinah Lee,1 Yun Ji Nam,1 Hyungu Kwon,1 Jaekyoung Son,5 Gowun Jeong,7 Ji-Hye Oh,3 Chang Ohk Sung,3 Eui Man Jeong,8 Jaehoon An,9,10 Sungho Won,9,10 Bumsik Hong,11 Jae Lyun Lee,12,* Yong Mee Cho,3,* and Dong-Myung Shin1,14,* 1Department of Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 2Pathology Center, Seegene Medical Foundation, Seoul 04805, Korea 3Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 4Department of Pathology, Ewha Womans University College of Medicine, Ewha Womans University Mokdong Hospital, Seoul 07985, Korea 5Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 6Center for Cell Therapy, Asan Medical Center, Seoul 05505, Korea 7AI Recommendation, T3K, SK Telecom, Seoul 04539, Korea 8College of Pharmacy, Jeju National University, Jeju 63243, Korea 9Department of Public Health Sciences, Seoul National University, Seoul 08826, Korea 10RexSoft, Inc. , Seoul 08826, Korea 11Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 12Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea 13These authors contributed equally 14Lead contact *Correspondence: [jaelyun@amc.seoul.kr](jaelyun@amc.seoul.kr) (J.L.L.), [yongcho@amc.seoul.kr](yongcho@amc.seoul.kr) (Y.M.C.), [d0shin03@amc.seoul.kr](d0shin03@amc.seoul.kr) (D.-M.S.) [https://doi.org/10.1016/j.xcrm.2023.101224](https://doi.org/10.1016/j.xcrm.2023.101224) SUMMARY 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

FAQs

Why is predicting response to preoperative cisplatin-based NAC in muscle-invasive bladder cancer still challenging?

Complete response rates are relatively low, and current clinicopathologic and molecular classifications are inadequate to reliably predict NAC response.

What does the study identify as fundamental to NAC resistance?

Dysregulation of the glutathione (GSH) pathway is shown to be fundamental for NAC resistance in muscle-invasive bladder cancer.

How do the findings suggest a therapeutic strategy beyond prediction?

GSH dynamics is linked to cisplatin resistance, and combination treatment using a GSH dynamics modulator with cisplatin significantly suppresses tumor growth in an orthotopic xenograft model.

Sep 24, 2026

Uploaded by Mimi