PD07-03 AN ORAL FIRST-IN-CLASS SMALL MOLECULE RSK INHIBITOR SUPPRESSES AR VARIANTS AND TUMOR GROWTH IN PROSTATE CANCER

Abstract

You have accessJournal of UrologyCME1 May 2022PD07-03 AN ORAL FIRST-IN-CLASS SMALL MOLECULE RSK INHIBITOR SUPPRESSES AR VARIANTS AND TUMOR GROWTH IN PROSTATE CANCER Masaki Shiota, Miho Ushijima, Takashi Matsumoto, Eiji Kashiwagi, Junichi Inokuchi, and Masatoshi Eto Masaki ShiotaMasaki Shiota More articles by this author , Miho UshijimaMiho Ushijima More articles by this author , Takashi MatsumotoTakashi Matsumoto More articles by this author , Eiji KashiwagiEiji Kashiwagi More articles by this author , Junichi InokuchiJunichi Inokuchi More articles by this author , and Masatoshi EtoMasatoshi Eto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Ribosomal S6 kinase has been shown to play a key role in the cellular resistance to endocrine therapy in prostate cancer through its regulation of YB-1/androgen receptor (AR) signaling. PMD-026, an oral first-in-class small molecule kinase inhibitor, is the first identified ribosomal S6 kinase inhibitor. This study investigated the effect of PMD-026 on YB-1/AR signaling and its antitumor effect in prostate cancer in vitro and in vivo. METHODS: Castration-resistant prostate cancer 22Rv1 cells that express high levels AR variants were used in this study. The effect of PMD-026 on YB-1/AR signaling was investigated by quantitative real-time PCR and western blot analysis. The effects of PMD-026 on prostate cancer cells were investigated by cytotoxicity analysis, apoptosis assay, and cell cycle assay in vitro and a mouse castration model in vivo. RESULTS: PMD-026 decreased YB-1 phosphorylation as well as AR V7 mRNA and AR variants expressions in 22Rv1 cells. PMD-026 suppressed cell proliferation alone and in combination with the second-generation antiandrogens enzalutamide and darolutamide by inducing cellular apoptosis and G2/M arrest. In a mouse xenograft model, PMD-026 suppressed tumor growth, and the combination of PMD-026 and enzalutamide inhibited tumor growth more prominently than single treatments. CONCLUSIONS: Our results demonstrate an excellent antitumor effect of the novel ribosomal S6 kinase inhibitor PMD-026 and the combination effect with the antiandrogen enzalutamide in castration-resistant prostate cancer. These findings warrant a clinical trial of PMD-026 in prostate cancer patients. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e98 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Masaki Shiota More articles by this author Miho Ushijima More articles by this author Takashi Matsumoto More articles by this author Eiji Kashiwagi More articles by this author Junichi Inokuchi More articles by this author Masatoshi Eto More articles by this author Expand All Advertisement PDF DownloadLoading ...