You have accessJournal of UrologyBladder Cancer: Basic Research1 Apr 20111054 HSP90 INHIBITORS POTENTIALLY OVERCOME CHEMORADIOTHERAPY RESISTANCE ASSOCIATED WITH HER2 AND NFfÈB OVEREXPRESSION IN MIBC Soichiro Yoshida, Fumitaka Koga, Manabu Tatokoro, Satoru Kawakami, Yasuhisa Fujii, Jiro Kumagai, Len Neckers, and Kazunori Kihara Soichiro YoshidaSoichiro Yoshida Tokyo, Japan More articles by this author , Fumitaka KogaFumitaka Koga Tokyo, Japan More articles by this author , Manabu TatokoroManabu Tatokoro Tokyo, Japan More articles by this author , Satoru KawakamiSatoru Kawakami Tokyo, Japan More articles by this author , Yasuhisa FujiiYasuhisa Fujii Tokyo, Japan More articles by this author , Jiro KumagaiJiro Kumagai Tokyo, Japan More articles by this author , Len NeckersLen Neckers Bethesda, MD More articles by this author , and Kazunori KiharaKazunori Kihara Tokyo, Japan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2011.02.1091AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES In chemoradiotherapy (CRT) based bladder-sparing protocols, patients who achieve complete response (CR) to induction CRT could be candidates for bladder preservation, while those with non-CR undergo radical cystectomy (RC) and have poorer prognosis. Prediction of non-CR patients and development of novel strategy to improve CRT response would bring these patients better QOL with bladder preservation and better oncological outcomes. We investigated molecules associated with CRT resistance and strategy to overcome the resistance by targeting these molecules. METHODS Associations between expression of radiation resistance-related proteins against which targeting agents are available (HER2, survivin, p53 and NFfÈB) and pathologic CRT response were assessed in 35 MIBC patients who underwent tumor biopsy but not debulking TUR, induction CRT and subsequently RC or partial cystectomy. Potential role of small molecules, which inactivate the CRT resistance-related proteins, in overcoming the CRT resistance was investigated in preclinical CRT models using bladder cancer cells (T24, UMUC-3 and 5637) and primarily cultured normal human urothelial cells (NHU). RESULTS On multivariate analysis, HER2 and nuclear NFfÈB overexpression significantly and independently associated with CRT resistance (pathological non-CR); a CR rate for MIBC positive for HER2 and/or NFfÈB was 15% (4/26) while that for dual-negative MIBC was 89% (8/9, p <.0001). Heat shock protein (Hsp) 90 inhibitors, being now evaluated in a phase 3 clinical trial for multiple myeloma, inactivate multiple oncoproteins including HER2 and NFfÈB by targeting a single molecular chaperone Hsp90. To overcome the CRT resistance, we investigated a role of Hsp90 inhibitors. All bladder cancer cell lines used overexpress both of HER2 and NFfÈB compared to NHU. Hsp90 inhibitors, which destabilized HER2 and inhibited NFfÈB activation without cytocidal effects, efficiently sensitized bladder cancer cells to in vitro CRT by enhancing apoptosis. Importantly, the sensitizing effects were not observed in NHU. Hsp90 inhibitors successfully potentiated response to in vivo CRT in mice UMUC-3 xenografts model. CONCLUSIONS Overexpression of HER2 and NFfÈB is relevant to CRT resistance in MIBC. Hsp90 inhibitors inactivate the both molecules and tumor-selectively potentiate CRT response. These results encourage clinical trials of Hsp90 inhibitors to overcome CRT resistance in patients with MIBC overexpressing HER2 and NFfÈB. © 2011 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 185Issue 4SApril 2011Page: e424 Advertisement Copyright & Permissions© 2011 by American Urological Association Education and Research, Inc.MetricsAuthor Information Soichiro Yoshida Tokyo, Japan More articles by this author Fumitaka Koga Tokyo, Japan More articles by this author Manabu Tatokoro Tokyo, Japan More articles by this author Satoru Kawakami Tokyo, Japan More articles by this author Yasuhisa Fujii Tokyo, Japan More articles by this author Jiro Kumagai Tokyo, Japan More articles by this author Len Neckers Bethesda, MD More articles by this author Kazunori Kihara Tokyo, Japan More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...