MP81-06 OVERCOMING CABAZITAXEL RESISTANCE BY G2/M REGULATING GENES IN CASTRATION-RESISTANT PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology III (MP81)1 Apr 2019MP81-06 OVERCOMING CABAZITAXEL RESISTANCE BY G2/M REGULATING GENES IN CASTRATION-RESISTANT PROSTATE CANCER Hiroshi Hongo*, Takeo Kosaka, Yoshinori Yanai, Yota Yasumizu, Yasumasa Miyazaki, Nobuyuki Tanaka, Kazuhiro Matsumoto, Ryuichi Mizuno, Eiji Kikuchi, and Mototsugu Oya Hiroshi Hongo*Hiroshi Hongo* More articles by this author , Takeo KosakaTakeo Kosaka More articles by this author , Yoshinori YanaiYoshinori Yanai More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki More articles by this author , Nobuyuki TanakaNobuyuki Tanaka More articles by this author , Kazuhiro MatsumotoKazuhiro Matsumoto More articles by this author , Ryuichi MizunoRyuichi Mizuno More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1097/01.JU.0000557425.64959.51AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVES: Recently, cabazitaxel (CBZ) was identified as the most effective cytotoxic agent to demonstrate an improvement in survival in men with docetaxel-refractory castration-resistant prostate cancer (CRPC). However, the survival benefit of CBZ for CRPC patients is limited to only a few months. Because CBZ-resistant CRPC has an extremely poor prognosis, establishment of a novel treatment for CBZ-resistant CRPC is greatly needed. The aim of this study was to explore drugs targeting the CBZ-resistance related genetic network by bioinformatic analysis and testing the antitumor effects of CBZ for resistant CRPC. METHODS: Two CRPC cell lines, DU145 and PC3, and two CBZ-resistant cell lines were used in this study. We performed screening tests for candidate drugs to inhibit the genetic network in CBZ-resistant CRPC using in silico analysis, and identified a candidate drug, KHO931 (Figure). The antitumor effect of KHO931 for CBZ-resistant cell lines was determined using mice xenograft tumor models. RESULTS: We incubated DU145 and PC3CR cells with gradually increasing concentrations of CBZ for 2 years and established the CBZ-resistant cell lines, DU145CR and PC3CR. We compared the cytotoxic effect of CBZ on DU145, PC3, DU145CR and PC3CR cells using a cell viability assay. The half maximal inhibitory concentration (IC50) of CBZ in CBZ-resistant cell lines was 3 times higher than that for parental cells. Cell cycle analysis demonstrated DU145CR and PC3CR had resistance to G2/M arrest induced by CBZ. Microarray analysis revealed gene clusters related to cell division were up-regulated in DU145CR and PC3CR. Next, we tested the anti-tumor effect of the candidate drug KHO931 for overcoming CBZ-resistance. KHO931 treatment had an anti-tumor effect in CBZ-resistant cell lines. Quantitative PCR revealed that KHO931 down-regulated mRNA expression of the Cytoskeleton (CSK)-related protein family, which regulates G2/M transition. A CSK-related protein inhibitor or genetic knockdown of CSK-related protein significantly suppressed cell proliferation of DU145CR and PC3CR. We tested the efficacy of KHO031 for CBZ resistance in mice xenograft models. KHO931 inhibited xenograft tumor growth in monotherapy. In addition, KHO931 and CBZ had a synergic effect on DU145CR and PC3CR xenograft tumors (Fig. B & C). These results suggest that KHO931 has potential for reprogramming CBZ-resistant CRPC. CONCLUSIONS: Targeting the G2/M regulation mechanism with KHO931 can overcome CBZ resistance in CRPC. Source of Funding: This study was supported by Grants-in-Aid for Scientific Research (#17K16813 to H. Hongo and #17K11158 to T. Kosaka) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan. Shinjuku-ku, Japan© 2019 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 201Issue Supplement 4April 2019Page: e1172-e1173 Advertisement Copyright & Permissions© 2019 by American Urological Association Education and Research, Inc.MetricsAuthor Information Hiroshi Hongo* More articles by this author Takeo Kosaka More articles by this author Yoshinori Yanai More articles by this author Yota Yasumizu More articles by this author Yasumasa Miyazaki More articles by this author Nobuyuki Tanaka More articles by this author Kazuhiro Matsumoto More articles by this author Ryuichi Mizuno More articles by this author Eiji Kikuchi More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement PDF downloadLoading ...