Student University of Ulsan College of Medicine, Republic of Korea
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. In previously study, we found that CDK1 phosphorylation of TFCP2L1, a pluripotency-associated transcription factor, orchestrated pluripotency and cell cycling in embryonic stem cells and was aberrantly activated in aggressive bladder cancers (Heo at al., 2019). Importantly, molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. In this study, we demonstrate that dysregulation of 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, identifying that GSH dynamics proteins, including glutaminase-1 (GLS), are associated with NAC resistance. GSH dynamics is activated in cisplatin-resistant MIBC cells and combination treatment with 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.
Funding Source: This research was supported by the National Research Foundation of Korea (NRF-2021R1A2C2005790, NRF-2019R1A2C1088246), the Ministry of Education (RS-2024-00448676, 2022R1I1A1A01066044).
