PD51-08 SREBP1 INDUCES RESISTANCE TO HIF-2α ANTAGONIST IN CLEAR CELL RENAL CELL CARCINOMA

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (PD51)1 May 2024PD51-08 SREBP1 INDUCES RESISTANCE TO HIF-2α ANTAGONIST IN CLEAR CELL RENAL CELL CARCINOMA Da Hyeon Son, Young Ju Lee, Hyo Eun Kim, Eun Song Kim, Sung Yul Park, and Young Eun Yoon Da Hyeon SonDa Hyeon Son , Young Ju LeeYoung Ju Lee , Hyo Eun KimHyo Eun Kim , Eun Song KimEun Song Kim , Sung Yul ParkSung Yul Park , and Young Eun YoonYoung Eun Yoon View All Author Informationhttps://doi.org/10.1097/01.JU.0001009360.84490.42.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Hypoxia-inducible factor-2α (HIF-2α) is a transcription factor that frequently accumulates in clear cell renal cell carcinoma (ccRCC), resulting in constitutive activation of genes involved in carcinogenesis. Belzutifan (MK-6482) has been developed as a potent and selective small molecule antagonist of HIF-2α, but resistance to this has been reported. We identified target gene that induce resistance to the HIF-2α antagonist and evaluated the mechanism and anticancer effect in ccRCC. METHODS: First, we produced a belzutifan-resistant ccRCC cell lines (786-O and A498) by gradually increasing the concentration of belzutifan (0.1μM∼10μM) for 3 months. The prepared belzutifan- resistant cell lines were confirmed for resistance using immunoprecipitation (IP) and proximity ligation assay (PLA). A xenograft models were produced by subcutaneously injecting belzutifan-sensitive (plain cell lines) and resistant cell lines, and belzutifan was orally administered 3 mg/kg every day for 3 weeks. To find the target that induces resistance to belzutifan, we performed RNA sequencing (RNA-seq) with tumor tissue of xenograft. Small molecule inhibitor of target gene was used to confirm the anticancer effect. RESULTS: In an experiment using IP and PLA, the binding of HIF-2α and HIF-1β was reduced by belzutifan treatment in plain 786-O and A498 cells, but this binding was not reduced by belzutifan treatment in belzutifan resistance 786-O and A498 cells. Also, in animal models, the size of tumors injected with plain cell lines was reduced by belzutifan, but the size of tumors injected with resistant cell lines did not appear to be reduced by belzutifan administration. Through RNA-seq analysis, we found that SREBP1, a transcription factor involved in lipid metabolism, was associated with belzutifan-resistance. Overexpression of SREBP1 protein and lipids was confirmed in belzutifan-resistance xenograft models. in vitro and in vivo mouse model, we confirmed that the combined treatment of the SREBP1 inhibitors fatostatin and belzutifan had an anti-tumor effect. CONCLUSIONS: In this study, we found the gene SREBP1, which is involved in inducing resistance to HIF-2α antagonists in ccRCC, and confirmed that co-administration of its inhibitors fatostatin and belzutifan has an anticancer effect. Download PPTDownload PPT Source of Funding: This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (2021R1F1A1064309) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e1067 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Da Hyeon Son More articles by this author Young Ju Lee More articles by this author Hyo Eun Kim More articles by this author Eun Song Kim More articles by this author Sung Yul Park More articles by this author Young Eun Yoon More articles by this author Expand All Advertisement PDF downloadLoading ...