172 PRECLINICAL EFFICACY OF AZD8055, A DUAL MTORC1/2 INHIBITOR, IN RCC HARBORING TFE3 GENE FUSIONS

Abstract

You have accessJournal of UrologyKidney Cancer: Basic Research (I)1 Apr 2013172 PRECLINICAL EFFICACY OF AZD8055, A DUAL MTORC1/2 INHIBITOR, IN RCC HARBORING TFE3 GENE FUSIONS Eric C. Kauffman, Soroush Rais-Bahrami, Gopal N. Gupta, Jeffrey W. Nix, Youfeng Yang, W. Marston Linehan, and Ramaprasad Srinivasan Eric C. KauffmanEric C. Kauffman Bethesda, MD More articles by this author , Soroush Rais-BahramiSoroush Rais-Bahrami Bethesda, MD More articles by this author , Gopal N. GuptaGopal N. Gupta Bethesda, MD More articles by this author , Jeffrey W. NixJeffrey W. Nix Bethesda, MD More articles by this author , Youfeng YangYoufeng Yang Bethesda, MD More articles by this author , W. Marston LinehanW. Marston Linehan Bethesda, MD More articles by this author , and Ramaprasad SrinivasanRamaprasad Srinivasan Bethesda, MD More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2013.02.1552AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Xp11 chromosomal translocations resulting in gene fusions of the TFE3 transcription factor gene comprise up to 5% of all renal cell carcinomas (RCC). TFE3-fusion RCC (TfRCC) is clinically aggressive with frequent metastasis. However, the key signaling pathways for therapeutic targeting remain under investigation, and no drug to date has shown in vivo efficacy in the preclinical setting. We investigated the preclinical efficacy of a dual mTORC1/mTORC2 inhibitor in TfRCC. METHODS Four genetically confirmed TfRCC patient cell lines established at the National Cancer Institute and one benign renal cortical epithelial cell line were treated in vitro with the mTORC1 inhibitor, sirolimus, or the mTORC1/mTORC2 inhibitor, AZD8055 (AstraZeneca). Cell proliferation and cytotoxicity were measured by MTT assay and lactate dehydrogenase (LDH) quantification, respectively. Athymic nude mice (n=40) with TfRCC cell line xenografts were subjected to 3-week treatments with weekly intraperitoneal (IP) sirolimus, daily oral (PO) AZD8055, or IP/PO vehicle controls. RESULTS AZD8055 had little effect on benign renal cells but potently inhibited TfRCC cell growth in vitro (IC50= 20-50 nM), with maximal inhibition of 80-90% at sub-micromolar concentrations, compared to 30-50% with sirolimus. Immunoblotting indicated more effective suppression of Akt/mTOR signaling with AZD8055 than sirolimus, with significant reductions in levels of phosphorylated Akt(S473) and 4EBP1 and HIF1alpha levels with the former. LDH assays suggested growth arrest, rather than cytotoxicity, as the predominant mechanism of AZD8055 growth suppression. In mouse xenograft studies, AZD8055 treatment significantly reduced mean TfRCC tumor size compared to sirolimus or vehicle controls (FIGURE; p<0.001). Median survival was significantly longer in mice treated with AZD8055 (52 days) compared to those receiving sirolimus (32 days, p<0.001) or vehicle control (33 days, p<0.001). CONCLUSIONS The Akt-mTOR pathway is a promising therapeutic target in TfRCC. In preclinical studies, dual mTORC1/2 inhibition with AZD8055 appears more effective than selective mTORC1 inhibition, possibly by overcoming feedback Akt-activation associated with the latter. These data provide the basis for further exploration of dual mTORC1/2 inhibitors in TfRCC. © 2013 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 189Issue 4SApril 2013Page: e70-e71 Advertisement Copyright & Permissions© 2013 by American Urological Association Education and Research, Inc.MetricsAuthor Information Eric C. Kauffman Bethesda, MD More articles by this author Soroush Rais-Bahrami Bethesda, MD More articles by this author Gopal N. Gupta Bethesda, MD More articles by this author Jeffrey W. Nix Bethesda, MD More articles by this author Youfeng Yang Bethesda, MD More articles by this author W. Marston Linehan Bethesda, MD More articles by this author Ramaprasad Srinivasan Bethesda, MD More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...