Abstract 5193: Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder cancer

Abstract

Abstract Cancer heterogeneity arises from cellular features, suggesting that distinct molecular drivers may be latent within cancers diagnosed at different clinicopathological stages. We thoroughly assessed phenotypic traits and molecular alterations linked to chemoresistance and constructed chemoresistant bladder cancer cell lines representing the stepwise transformation. Model cell lines (5637GRCs, gemcitabine-resistant cells) with stepwise gemcitabine resistance representing early, intermediate, and late resistance phases were developed from non-muscle-invasive bladder cancer (NMIBC) cells. Notably, an increase in cell motility was observed at a relatively early phase. The results from the time-course analysis of molecular evolution showed changes in focal adhesion kinase signaling, PI3K-Akt signaling, and TGF-β signaling pathways during the phase of increasing cell motility. As chemoresistance increased, the levels of genes related to differentiation and MAPK signaling gradually increased. A 63-gene chemoresistance-motility (CrM) signature was constructed and weighted according to cell motility, and a strong correlation was observed between cancer metastasis and drug resistance; the signature also showed prognostic relevance in patients with NMIBC. This study affords a significant understanding of the molecular evolution of chemoresistance acquisition and enables prediction of cancer progression during chemotherapy treatment. Moreover, it provides insights into the progression of cells through all chemoresistance stages from NMIBC to MIBC. Therefore, this study proposes the feasibility of utilizing biomarkers correlated with cancer motility to predict cancer progression in the early phase of chemotherapeutic intervention in patients with non-muscle-invasive bladder cancer. Citation Format: Gi-Eun Yang, Jae-Jun Kim, Tae Hwan Shin, Sun-Hee Leem. Molecular evolution of chemoresistance acquisition and predictive insights into the progression of bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5193.