Mp05-18 Amino Acid Transport Inhibition Resensitizes Enzalutamide-Resistant Prostate Cancer Cells to Enzalutamide

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP05)1 May 2024MP05-18 AMINO ACID TRANSPORT INHIBITION RESENSITIZES ENZALUTAMIDE-RESISTANT PROSTATE CANCER CELLS TO ENZALUTAMIDE Sayani Bhattacharjee, Rebecca R. Wynn, Puneet Sindhwani, Firas G. Petros, and Nagalakshmi Nadiminty Sayani BhattacharjeeSayani Bhattacharjee , Rebecca R. WynnRebecca R. Wynn , Puneet SindhwaniPuneet Sindhwani , Firas G. PetrosFiras G. Petros , and Nagalakshmi NadimintyNagalakshmi Nadiminty View All Author Informationhttps://doi.org/10.1097/01.JU.0001008740.27639.cc.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Castration-resistant prostate cancer (CRPC) cells develop resistance to enzalutamide within a relatively short span of time. Several mechanisms have been proposed to contribute to the development of resistance to enzalutamide. These include androgen receptor variants, alternative signaling mechanisms, metabolic pathways, androgen receptor by-pass mechanisms etc. Our previous studies showed that metabolic alterations during the development of resistance to enzalutamide may offer unique opportunities to target metabolic vulnerabilities in prostate cancer (PCa) cells. Exploration of the mechanisms involved by metabolomics indicated that amino acid metabolism and amino acid transporters may play an important role in the acquisition of resistance to enzalutamide. Hence, we tested whether co-targeting amino acid transport resensitizes enzalutamide-resistant PCa cells to enzalutamide. METHODS: We analyzed the expression levels of amino acid transporters in PCa tissues using public datasets. We treated enzalutamide-sensitive and -resistant PCa cells with varying concentrations of amino acid transport inhibitors JPH203 or V9302 either singly or in combination with enzalutamide and assessed cell survival, cell viability, proliferation, and survival in 3-D models. We analyzed synergism between the combinations using SynergyFinder. RESULTS: We found that expression levels of several amino acid transporters are increased in PCa tissues. We also found that amino acid transporter expression is significantly upregulated in enzalutamide-resistant PCa cells. Treatment with amino acid transport inhibitors JPH203 and V9302 inhibited enzalutamide-resistant PCa cell survival preferentially. Co-treatment with amino acid transport inhibitors and enzalutamide resensitized enzalutamide-resistant PCa cells to enzalutamide. CONCLUSIONS: Our results indicate that increasing amino acid import may be one of the metabolic mechanisms employed by PCa cells during the acquisition of resistance to enzalutamide. These results imply that inhibiting elevated amino acid import into cancer cells may be an attractive modality to overcome enzalutamide resistance. Source of Funding: Department of Defense Prostate Cancer Research Program IDEA Development Award PC190332 (W81XWH-20-1-0794) © 2024 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 211Issue 5SMay 2024Page: e49 Advertisement Copyright & Permissions© 2024 by American Urological Association Education and Research, Inc.Metrics Author Information Sayani Bhattacharjee More articles by this author Rebecca R. Wynn More articles by this author Puneet Sindhwani More articles by this author Firas G. Petros More articles by this author Nagalakshmi Nadiminty More articles by this author Expand All Advertisement PDF downloadLoading ...