PD17-07 COMBINATION THERAPY FOR TKI RESISTANT KIDNEY CANCER VIA BLOCKING ERΒ/CIRCRNA-DGKD/MIR-125-5P/VE-CADHERIN SIGNAL INDUCED VASCULOGENIC MIMICRY

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD17-07 COMBINATION THERAPY FOR TKI RESISTANT KIDNEY CANCER VIA BLOCKING ERΒ/CIRCRNA-DGKD/MIR-125-5P/VE-CADHERIN SIGNAL INDUCED VASCULOGENIC MIMICRY Jie Ding, Yixi Hu, Chawnshang Chang, Edward M. Messing, Jean Joseph, and Shuyuan Yeh Jie DingJie Ding More articles by this author , Yixi HuYixi Hu More articles by this author , Chawnshang ChangChawnshang Chang More articles by this author , Edward M. MessingEdward M. Messing More articles by this author , Jean JosephJean Joseph More articles by this author , and Shuyuan YehShuyuan Yeh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003272.07AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Tyrosine kinase inhibitors (TKIs), pazopanib and sunitinib, are widely used in renal cell carcinoma (RCC) therapy by inhibiting tumor angiogenesis. However, most patients become insensitive or develop resistance toward TKI therapy eventually, and the underlying mechanisms have not yet been fully elucidated. Our goal is to reveal the molecular mechanisms of TKI resistant RCC to find a potential combination therapy for TKI-resistant RCC. METHODS: The human RCC cell lines: 786-O, A498, Caki-1, and SW-839 were used. Lentiviral plasmids were used to generate gene engineering tools. The qPCR and Western blot were used to evaluate the gene expressions at RNA and protein levels, respectively. Vasculogenic mimicry (VM) assays were performed to examine vascular-like structure formation ability of cancer cells. Protein-DNA binding complexes were detected by Chromatin immunoprecipitation (ChIP) assays. The human DGKD promoter region was cloned into pGL3 vector for Luciferase Assays. Preclinical mouse RCC model was used to evaluate the anti-cancer effect of pazopanib and circRNA-DGKD blockage in TKI resistant RCC. RESULTS: TKI resistant RCC cells showed increased ability of forming VM to counteract the TKI-suppression function both in vivo and in vitro. Mechanism dissection revealed that pazopanib (or sunitinib)-resistant RCC cells had an increased ERβ, consequently enhancing the circRNA-DGKD expression. In turn, circRNA-DGKD could increase VE-cadherin expression via sponging the miR-125-5p. Supportively, targeting circRNA-DGKD intercepted the RCC VM formation, reduced metastases and improved survival in an orthotopic RCC mouse model. Collectively, the findings may aid in the development of novel therapies for metastatic or TKI-resistant RCC. CONCLUSIONS: Our study reveals that the resistance to TKIs (pazopanib or sunitinib) occurs by increasing vasculogenic mimicry (VM) ability to counteract the TKI angiogenesis suppression function. Furthermore, we find a potential therapy to more effectively treat TKI resistant RCC by blocking ERβ/circRNA-DGKD/miR-125-5p/VE-cadherin pathway together with pazopanib administration. Source of Funding: This work was partially supported by URMC Urology Department Research fund and George H. Whipple Professorship Endowment © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e498 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jie Ding More articles by this author Yixi Hu More articles by this author Chawnshang Chang More articles by this author Edward M. Messing More articles by this author Jean Joseph More articles by this author Shuyuan Yeh More articles by this author Expand All Advertisement PDF downloadLoading ...