MP37-02 NUTLIN-3A AS A NOVEL ANTICANCER AGENT FOR ADRENOCORTICAL CARCINOMA WITH CTNNB1 MUTATION

You have accessJournal of UrologyAdrenal1 Apr 2017MP37-02 NUTLIN-3A AS A NOVEL ANTICANCER AGENT FOR ADRENOCORTICAL CARCINOMA WITH CTNNB1 MUTATION Chenchen Feng and Shanwen Chen Chenchen FengChenchen Feng More articles by this author and Shanwen ChenShanwen Chen More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.1134AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Adrenocortical carcinoma (ACC) is a rare malignancy characterized with poor survival at advanced and metastatic stage, with no curative treatment available. CTNNB1 is frequently mutated in ACC and is identified as one of the driver mutations. Current targeted therapy for CTNNB1 in ACC is lacking and our study aims to screening for effective agents with antineoplastic activity against ACC with CTNNB1 mutation. METHODS In silico screening of the Genomics of Drug Sensitivity in Cancer (GDSC) database that included drug sensitivity data of 265 compounds in 1,074 cancer cells were conducted. Drug sensitivity in cells with CTNNB1 mutation was analyzed, and further in vitro and in vivo studies were performed using the compound. RESULTS Only one compound, Nutlin-3a, an MDM2 inhibitor was significantly sensitive in 18 cancer cells with CTNNB1 mutation. However, mutation of TP53, which was also common in ACC conferred significant resistance to Nutlin-3a. Further analysis of the 18 cells revealed no significant efficacy between cells with both CTNNB1 and TP53 mutation indicating concomitant TP53 mutation did not impact on drug efficacy. We verified Nutilin-3a-inhibited cellular proliferation in ACC cell line NCI- H295R which harbored CTNNB1 mutation but not in SW13 cells which did not. Nutlin-3a induced cell apoptosis and G1 cell- cycle arrest in NCI-H295R cells. Nutlin-3a also decreased cellular migration and inhibited epithelial-to-mesenchymal transition (EMT) process in terms of EMT index. Moreover, Nutlin-3a resulted in decreased beta-Catenin level independent of p53 level in NCI-H295R but not SW13 cells. We also evaluated the effect of Nutlin-3a on hormonal secretion of NCI-H295R cells and found it resulted in decreased levels of cortisol, androgen, and progesterone. Nutlin-3a treatment inhibited ACC tumor growth and hormonal secretion with no observed toxicity in mice in vivo. CONCLUSIONS Our study revealed Nutlin-3a, the first-generation MDM2 inhibitor potently inhibited ACC with CTNNB1 mutation. Several new derivatives of Nutlin-3a has now entered clinical trials, holding promise for targeted MDM2 inhibition in CTNNB1-mutant ACC. However, how p53/MDM2 axis coordinate with Wnt/beta-Catenin signaling in ACC warrants further study. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e475 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Chenchen Feng More articles by this author Shanwen Chen More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...