MP83-02 OVERCOMING PI3K/MTOR INHIBITOR RESISTANCE BY PIM1 INHIBITOR THROUGH REGULATION OF TYROSINE KINASE EXPRESSION.

Abstract

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology II1 Apr 2017MP83-02 OVERCOMING PI3K/MTOR INHIBITOR RESISTANCE BY PIM1 INHIBITOR THROUGH REGULATION OF TYROSINE KINASE EXPRESSION. Takeo Kosaka, Hiroshi Hongo, Yota Yasumizu, Yasumasa Miyazaki, Eiji Kikuchi, Akira Miyajima, and Mototsugu Oya Takeo KosakaTakeo Kosaka More articles by this author , Hiroshi HongoHiroshi Hongo More articles by this author , Yota YasumizuYota Yasumizu More articles by this author , Yasumasa MiyazakiYasumasa Miyazaki More articles by this author , Eiji KikuchiEiji Kikuchi More articles by this author , Akira MiyajimaAkira Miyajima More articles by this author , and Mototsugu OyaMototsugu Oya More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.2570AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Recently we demonstrated that the activated PI3K-Akt-mTOR signaling pathway induced by androgen deprivation therapy or docetaxel explains at least in part the aggressiveness in CRPC. Inhibitors of PI3K-Akt-mTOR signaling pathway have potential as next generation anti-CRPC drug. However, there have been little reports that monotherapy with a PI3K-Akt-mTOR signaling inhibitor was effective to CRPC. PIM1 is a kinase which induces expression of receptor tyrosine kinases and it has been reported to contribute Akt inhibitor resistance in lymphoma. We investigated the anti-tumor effect of PIM1 inhibitor for CRPC. METHODS Two cell lines were used: LNCaP, a androgen-dependent PCa cell line with PTEN deficiency; and C4-2AT6, a castration-resistant prostate cancer cell line with PTEN deficiency and elevated Akt signaling pathways. We investigated the therapeutic efficacy of PIM1 inhibitor; AZD1208 and PI3K/mTOR dual inhibitor; BEZ235. RESULTS We compared the cytotoxic effect of docetaxel (DTX) on LNCaP and C4-2AT6 cells by cell viability assay. In LNCaP and C4-2AT6 cells, the relative cell viability treated with 1nM DTX was 68.8 % ± 0.1 % and 87.5% ± 1.9 %, respectively. These results indicated that C4-2AT6 cells showed significantly higher resistance to DTX than LNCaP cells. Next we examined the cytotoxic effect of BEZ235 on LNCaP and C4-2AT6 cells by cell viability assay. In LNCaP and C4-2AT6 cells, the relative cell viability treated with 10nM BEZ235 was 90.2% ± 0.7 % and 89.9% ± 2.3 %, respectively. Western blotting showed increased expression of PIM1 and EGFR in BEZ235 treated cells. These results indicated that PI3K/mTOR inhibitor induced EGFR expression through PIM1 up-regulation. We evaluated the cytotoxic effect of AZD1208 on LNCaP and C4-2AT6. The relative cell viability was 67.9 ± 1.0 % and 67.5 ± 3.1 % with 10μM AZD1208, respectively. AZD1208 significantly inhibited cell proliferation of LNCaP and C4-2AT6. In addition, we examined synergic effect of AZD1208 and DTX/BEZ235. The relative cell viability treated with 10μM AZD1208 and 1nM DTX was 63.8 ± 1.1 % and 48.0 ± 0.6 %. The relative cell viability treated with 10μM AZD1208 and BEZ235 was 55.9 ± 1.6 % and 46.9 ± 1.5 %. We found AZD1208 also had synergic effect with DTX and BEZ235 (Figure). CONCLUSIONS PIM1 inhibition can overcome the drug resistant mechanism induced by targeting PI3K/Akt/mTOR pathways in docetaxel resistant CRPC. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e1106 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Takeo Kosaka More articles by this author Hiroshi Hongo More articles by this author Yota Yasumizu More articles by this author Yasumasa Miyazaki More articles by this author Eiji Kikuchi More articles by this author Akira Miyajima More articles by this author Mototsugu Oya More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...