MP04-11 TARGETING GLUTAMINE ADDICTION WITH POTENT DRUG COMBINATION THERAPY FOR RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyCME1 Apr 2023MP04-11 TARGETING GLUTAMINE ADDICTION WITH POTENT DRUG COMBINATION THERAPY FOR RENAL CELL CARCINOMA Yoshinari Muto, Akihito Takeuchi, Kenji Zennami, Eiji Sugihara, Ryoichi Shiroki, Hideyuki Saya, and Makoto Sumitomo Yoshinari MutoYoshinari Muto More articles by this author , Akihito TakeuchiAkihito Takeuchi More articles by this author , Kenji ZennamiKenji Zennami More articles by this author , Eiji SugiharaEiji Sugihara More articles by this author , Ryoichi ShirokiRyoichi Shiroki More articles by this author , Hideyuki SayaHideyuki Saya More articles by this author , and Makoto SumitomoMakoto Sumitomo More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003215.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The glutamine-dependent nature of cancer cells could be used as a new strategy for treating cancers that do not have drug-driver genes, such as renal cell carcinoma (RCC). We recently reported that Alanine-serine-cysteine transporter 2 (ASCT2) is associated with metastatic progression and survival in RCC. However, the administration of V9302, a specific inhibitor of ASCT2, raised the issue that intracellular glutamine levels are increased by a compensatory mechanism (presented at 2021 AUA annual meeting). In the present study, we investigated whether the combination strategy that effectively targets glutamine addiction would be effective as a treatment for RCC. METHODS: The human RCC cell lines, 786-O and 769-P were used. The protein expression was detected by Western blotting. Cell viability was assessed using WST-8 assay. Intracellular concentrations of glutamine and glutamate were analyzed using liquid chromatography-mass spectrometry (LC/MS). V9302 was used as the specific ASCT2 inhibitor and CB839 as the specific GLS inhibitor. As the xenograft model in vivo, athymic nude mice were injected subcutaneously with 786-O cells and given various doses of V9302 and CB839 intraperitoneally. RESULTS: LC/MS assays showed that intracellular glutamine levels in the RCC cell line increased after 48 hours of treatment with V9302 alone, but that glutamine levels were significantly reduced by the combination of V9302 and CB839. Western blot analysis showed that the expression levels of ASCT2 and GLS1 were both decreased after the combination therapy. The tumor xenograft study confirmed that the combination of V9302 (30 mg/kg, intraperitoneal injection) and CB839 (20 mg/kg, intraperitoneal injection) significantly inhibited 786-O tumor growth compared with controls within 3 weeks after treatment (p<0.001). CONCLUSIONS: Our results suggest that V9302 monotherapy is insufficient for the treatment of RCC but that a novel combination strategy using CB839 in addition to V9302 could overcome the tolerance for the monotherapy and effectively target glutamine addiction in RCC. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e37 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yoshinari Muto More articles by this author Akihito Takeuchi More articles by this author Kenji Zennami More articles by this author Eiji Sugihara More articles by this author Ryoichi Shiroki More articles by this author Hideyuki Saya More articles by this author Makoto Sumitomo More articles by this author Expand All Advertisement PDF downloadLoading ...