PD43-03 MCT INHIBITION SYNERGIZES WITH TYROSINE KINASE AND MTOR INHIBITOR TREATMENT IN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyCME1 May 2022PD43-03 MCT INHIBITION SYNERGIZES WITH TYROSINE KINASE AND MTOR INHIBITOR TREATMENT IN RENAL CELL CARCINOMA Bhaghyasree Jambunathan, Abdo Dergham, Sayani Bhattacharjee, Rebecca Wynn, Puneet Sindhwani, Firas Petros, and Nagalakshmi Nadiminty Bhaghyasree JambunathanBhaghyasree Jambunathan More articles by this author , Abdo DerghamAbdo Dergham More articles by this author , Sayani BhattacharjeeSayani Bhattacharjee More articles by this author , Rebecca WynnRebecca Wynn More articles by this author , Puneet SindhwaniPuneet Sindhwani More articles by this author , Firas PetrosFiras Petros More articles by this author , and Nagalakshmi NadimintyNagalakshmi Nadiminty More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002604.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: RCC has been recognized in recent years as a uniquely metabolic disease. All histologic types of RCC exhibit increase in aerobic glycolysis with disease progression. The TCGA-RCC study showed that high grade, high stage, and low survival are associated with a shift to aerobic glycolysis and a decrease in oxidative phosphorylation. Approaches targeting glucose metabolism in RCC such as GLUT1 inhibitors, hexokinase inhibitors, GAPDH inhibitor, and PKM2 inhibitor showed limited clinical benefit. Monocarboxylate transporters (MCTs) play a major role in the export/import of the glycolytic end-product lactate. Different MCT isoforms are differentially expressed in RCC tissues with an increase in the expression of MCT1 and MCT4 in clear-cell RCC and papillary RCC. Here we hypothesized that MCT inhibition may be an attractive therapeutic strategy against RCC cells. METHODS: We analyzed the expression levels of MCTs in RCC tissues using public datasets from Oncomine. We treated normal renal epithelial and renal cell carcinoma cells with varying concentrations of MCT inhibitors AR-C155858, AZD3965, or syrosingopine either singly or in combination with sunitinib or everolimus and assessed cell survival, cell viability, proliferation, clonogenic ability, survival in 3-D models, and glycolytic activity. We treated xenografts of ccRCC cells in mice with MCT inhibitors, sunitinib, or everolimus singly or in combination and assessed tumor growth. RESULTS: We found that the suppression of MCT activity using the MCT antagonists AR-C155858, AZD3965, or syrosingopine not only diminished the proliferation, survival, and clonogenic ability of RCC cells, but also potentiated the response of RCC cells to treatment with sunitinib or everolimus. MCT inhibitors inhibited the metabolic adaptation of ccRCC cells when treated with sunitinib or everolimus. Tumor growth of ccRCC xenografts was suppressed significantly when treated with a combination of MCT inhibitors with sunitinib or everolimus. These findings imply that MCT inhibition may be an effective strategy to develop combinatorial therapies in renal cell carcinoma. CONCLUSIONS: MCT inhibition may improve the anti-tumor effects of tyrosine kinase or mTOR inhibitors in renal cell carcinoma. Source of Funding: DoD-PCRP PC190332 (W81XWH2010794), University of Toledo College of Medicine and Life Sciences, NIH/NCI 1R21CA202404, NIH/NCI 1R03CA198696 © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e702 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Bhaghyasree Jambunathan More articles by this author Abdo Dergham More articles by this author Sayani Bhattacharjee More articles by this author Rebecca Wynn More articles by this author Puneet Sindhwani More articles by this author Firas Petros More articles by this author Nagalakshmi Nadiminty More articles by this author Expand All Advertisement PDF DownloadLoading ...