Pd14-08 Identification of a Bladder Cancer Subpopulation That May Benefit From Dasatinib

You have accessJournal of UrologyBladder Cancer: Basic Research & Pathophysiology II (PD14)1 May 2024PD14-08 IDENTIFICATION OF A BLADDER CANCER SUBPOPULATION THAT MAY BENEFIT FROM DASATINIB Shi Fu, Haifeng Wang, Jiansong Wang, and Junhao Chen Shi FuShi Fu , Haifeng WangHaifeng Wang , Jiansong WangJiansong Wang , and Junhao ChenJunhao Chen View All Author Informationhttps://doi.org/10.1097/01.JU.0001009472.76470.8c.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cancer progression involves the acquisition of stem-like characteristics that are associated with immune escape and drug resistance. Thus, molecular subtyping based on stemness characteristics of bladder cancer (BC) can help reveal intra-tumor heterogeneity and provide more precise therapeutic methods. METHODS: The stemness indices of each sample in BLCA cohort were computed using the one-class logistic regression algorithm and patients were classified using the unsupervised consensus clustering. Then, we gathered a total of 661 treatment-naïve samples from three datasets (BLCA, GSE31684, and GSE13507) to construct and validate a stemness-related prognostic index (SRPI) using Cox regression, LASSO regression and Random Forest methods. The IMvigor210 and GSE176307 cohorts, including 401 urothelial carcinoma patients treated with PD-1 or PD-L1 inhibitor, were employed to predict immunotherapy response. Afterwards, Gene expression data and their corresponding drug IC50 values for BC cell lines were collected from three datasets (GDSC, PRISM and CTRP). Sensitive drugs were screened for high-risk patients by multi-step strategies. Several in-vitro experiments and PDX model were used to confirm the drug efficacy and toxicity. RESULTS: BC patients were classified into two stemness subtypes with distinct prognosis, functional annotations, genomic variations, and immune profiles. Using the SRPI, we identified a high-risk subgroup of patients who had poorer prognosis, lower tumor mutational burden, a higher proportion of LumP/LumU subtype, activation of EMT pathway, inhibition of DDR pathway, and characteristics of immune exclusion. This high-risk subgroup responded poorly to immunotherapy and were insensitive to commonly used chemotherapeutic agents, FGFR inhibitors, and EGFR inhibitors. We further identified dasatinib as a sensitive agent for this high-risk subgroup. Finally, we confirmed that dasatinib significantly inhibited the growth of BC cells and tumors with higher SRPI. CONCLUSIONS: This study provides a novel subtyping of bladder cancer based on stemness signatures and demonstrates that SRPI is a promising tool for predicting prognosis and therapeutic opportunities for BC patients. With SRPI, we can identify a BC subpopulation that may benefit from dasatinib. Download PPT Source of Funding: The National Natural Science Foundation of China (Grant No. 82060464, Grant No. 82260609) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e356 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Shi Fu More articles by this author Haifeng Wang More articles by this author Jiansong Wang More articles by this author Junhao Chen More articles by this author Expand All Advertisement PDF downloadLoading ...