MP18-18 P53 IS INVOLVED IN RESISTANCE TO SUNITINIB IN RENAL CELL CARCINOMA

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology II (MP18)1 Apr 2020MP18-18 P53 IS INVOLVED IN RESISTANCE TO SUNITINIB IN RENAL CELL CARCINOMA Yohei Sekino*, Xiangrui Han, Keisuke Goto, Shogo Inoue, Tetsutaro Hayashi, Jun Teishima, Taniyama Daiki, Naoya Sakamoto, Kazuhiro Sentani, Naohide Oue, Wataru Yasui, and Akio Matsubara Yohei Sekino*Yohei Sekino* More articles by this author , Xiangrui HanXiangrui Han More articles by this author , Keisuke GotoKeisuke Goto More articles by this author , Shogo InoueShogo Inoue More articles by this author , Tetsutaro HayashiTetsutaro Hayashi More articles by this author , Jun TeishimaJun Teishima More articles by this author , Taniyama DaikiTaniyama Daiki More articles by this author , Naoya SakamotoNaoya Sakamoto More articles by this author , Kazuhiro SentaniKazuhiro Sentani More articles by this author , Naohide OueNaohide Oue More articles by this author , Wataru YasuiWataru Yasui More articles by this author , and Akio MatsubaraAkio Matsubara More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000000843.018AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Although approximately 70% of the patients show initial response with sunitinib in renal cell carcinoma (RCC), eventually sunitinib resistance occurred. Therefore there is an urgent need to clarify the mechanisms of sunitinib resistance. The tumor protein p53 is involved in chemo-resistance in several cancer. The aim of this study is to examine the expression and functional role of P53 on sunitinib resistance and a possible role of combination with MDM2 inhibitor: nutlin3 and sunitinib in RCC. METHODS: We established sunitinib resistance RCC cell lines. We analyzed the expression of P53 in sunitinib resistance cell lines and examined the effect of P53 knockout on sunitinib resistance. We also investigated the effect of combination with sunitinib and nutlin3. Expression of P53 in 49 RCC tissues treated with sunitinib was determined by immunohistochemisty. RESULTS: We established sunitinib resistance cells in Caki-1 and ACHN cells by culturing cells with increasing concentrations of sunitinib. Western blotting showed that the expression of P53 was decreased in sunitinib resistant cells compared with that in parental cells. Then, we generated the P53 knockout cells in Caki-1 and ACHN cells by CRISPR-cas9 system. Knockout of P53 promoted sunitinib resistance. Mdm2 is an important negative regulator of the p53. Therefore we examined the effect of combination therapy with sunitinib and nutlin3. Sunitinib alone had little effect on cell viability in the sunitinib resistant cell lines. However, the combination of sunitinib and nutlin3 significantly reduced cell viability in the sunitinib resistant cells. Western blotting revealed that the expression of P53 was induced by combination therapy with suniitnib and nutlin3 compared to nutlin3 treatment alone in sunitinib resistant cells. Additionally, we investigated the expression of P53 in 52 ccRCC cases treated with sunitinib treatment. A Kaplan-Meier analysis showed that the positive cases of P53 were associated with poor prognosis after sunitinib treatment (P = 0.04) (Fig. 1). CONCLUSIONS: The expression of P53 was downregulated in sunitinib resistant RCC cell lines. Knockout of P53 promoted sunitinib resistance. Nutlin3 re-sensitized sunitinib resistant cells to sunitinib treatment. These results suggest that the combination therapy with sunitinib and nutlin3 may be promising in RCC. Source of Funding: I have nothing to disclose © 2020 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 203Issue Supplement 4April 2020Page: e242-e242 Advertisement Copyright & Permissions© 2020 by American Urological Association Education and Research, Inc.MetricsAuthor Information Yohei Sekino* More articles by this author Xiangrui Han More articles by this author Keisuke Goto More articles by this author Shogo Inoue More articles by this author Tetsutaro Hayashi More articles by this author Jun Teishima More articles by this author Taniyama Daiki More articles by this author Naoya Sakamoto More articles by this author Kazuhiro Sentani More articles by this author Naohide Oue More articles by this author Wataru Yasui More articles by this author Akio Matsubara More articles by this author Expand All Advertisement PDF downloadLoading ...