PD24-08 SEQUENTIAL USAGE OF MTOR INHIBITOR FOLLOWED BY IMMUNOTHERAPIES FOR CABOZANTINIB-RESISTANT METASTATIC CLEAR CELL RENAL CELL CARCINOMAS

Abstract

You have accessJournal of UrologyCME1 Apr 2023PD24-08 SEQUENTIAL USAGE OF MTOR INHIBITOR FOLLOWED BY IMMUNOTHERAPIES FOR CABOZANTINIB-RESISTANT METASTATIC CLEAR CELL RENAL CELL CARCINOMAS Jee Soo Park, Myung Eun Lee, Won Sik Jang, Jongchan Kim, Se Mi Park, and Won Sik Ham Jee Soo ParkJee Soo Park More articles by this author , Myung Eun LeeMyung Eun Lee More articles by this author , Won Sik JangWon Sik Jang More articles by this author , Jongchan KimJongchan Kim More articles by this author , Se Mi ParkSe Mi Park More articles by this author , and Won Sik HamWon Sik Ham More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003302.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Cabozantinib, a multitargeted tyrosine kinase inhibitor (TKI), is an important option for the treatment of advanced clear cell renal cell carcinoma (accRCC), used as the first-line setting for intermediate- or poor-risk metastatic ccRCC, when immunotherapy is not available. We explored the underlying signaling pathway associated with the cabozantinib resistance and provided the optimal sequencing. METHODS: Cabozantinib-resistant RCC (CaR) cell lines were established by long-term treatment with cabozantinib. The mRNA expression profiles of PD-L1 and PI3K/AKT/mTOR signaling pathway proteins were investigated and compared in CaR and cabozantinib-sensitive (CaS) cell lines. Pulmonary metastatic orthotopic murine mRCC models have been developed with CaR Renca and CaS Renca. Mice were randomized and treated as 4 groups; 1) control (PBS treatment), 2) combination immunotherapy (anti-PD-1 and anti-CTLA-4 antibodies), 3) everolimus, and 4) sequential treatment of everolimus and followed by combination immunotherapy. RESULTS: All CaR cell lines demonstrated significant decreased in PD-L1 compared to CaS cell lines (p<0.05). Furthermore, the mRNA expression of major PI3K/AKT/mTOR pathway members, including PIK3CB, AKT3, and mTORC2 were increased in CaR Renca compared to CaS Renca. Everolimus treatment significantly increased PD-L1 expression in CaR Renca compared to CaS Renca. For murine mRCC models, CaR Renca model demonstrated significantly increased primary tumor growth, but decreased pulmonary metastasis compared to CaS Renca model. The best therapeutic benefits were obtained in group 4. CONCLUSIONS: We showed that cabozantinib decrease PD-L1 expression, while increase PI3K/AKT/mTOR signaling. Furthermore, mTOR inhibitor increased the PD-L1 expression in CaR cell line demonstrating that everolimus followed by combination immunotherapy can be the best subsequent treatment in CaR accRCC. Source of Funding: This work was supported by a grant from the Korea Health Technology R&D Project through the Korea Health Industry Development Institute funded by the Ministry of Health & Welfare, Republic of Korea [grant number: HI17C1095], and the National Research Foundation of Korea (NRF) grant funded by the Korean government (MSIT) [grant number: 2019R1A2C1002863 and 2022R1A2C2003831] © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e725 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jee Soo Park More articles by this author Myung Eun Lee More articles by this author Won Sik Jang More articles by this author Jongchan Kim More articles by this author Se Mi Park More articles by this author Won Sik Ham More articles by this author Expand All Advertisement PDF downloadLoading ...