893 DEFINING THE MOLECULAR DETERMINANTS OF SENSITIVITY TO EGFR INHIBITION IN UROTHELIAL CARCINOMA

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You have accessJournal of UrologyBladder Cancer: Basic Research II1 Apr 2012893 DEFINING THE MOLECULAR DETERMINANTS OF SENSITIVITY TO EGFR INHIBITION IN UROTHELIAL CARCINOMA Ian Udell, Raj Kurpad, Angela Smith, Matthew Nielsen, Raj Pruthi, Eric Wallen, Michael Woods, and William Kim Ian UdellIan Udell Chapel Hill, NC More articles by this author , Raj KurpadRaj Kurpad Chapel Hill, NC More articles by this author , Angela SmithAngela Smith Chapel Hill, NC More articles by this author , Matthew NielsenMatthew Nielsen Chapel Hill, NC More articles by this author , Raj PruthiRaj Pruthi Chapel Hill, NC More articles by this author , Eric WallenEric Wallen Chapel Hill, NC More articles by this author , Michael WoodsMichael Woods Chapel Hill, NC More articles by this author , and William KimWilliam Kim Chapel Hill, NC More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.988AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES EGFR is over−expressed in urothelial carcinomas (UC) and has been shown to correlate with increasing stage and grade as well as a decreased progression−free and overall survival. Multiple EGFR inhibitors are FDA approved and a phase II clinical trial of neoadjuvant erlotinib in patients with muscle invasive UC suggested possible clinical activity. We hypothesized that we could define molecular determinants of sensitivity or resistance to EGFR inhibition in UC by assessing if EGFR−associated gene expression signatures are predictive of response to erlotinib. METHODS Correlative tumor samples from a phase II clinical trial of neoadjuvant erlotinib in muscle invasive UC of the bladder were analyzed to define molecular determinants in response to EGFR inhibition. An in vitro EGFR−associated signature was developed and then evaluated on primary human bladder tumors. Several candidate molecular determinants of sensitivity to EGFR inhibition were characterized and examined for their ability to predict resistance to EGFR inhibitors. RESULTS While our in vitro EGFR−associated gene expression profile did not have predictive value in our tumor set, AKT2, MAPK6 and HRAS were significantly elevated in non−pT0 patients relative to pT0 patients, suggesting that increased EGFR signaling may be predictive of resistance to EGFR inhibitors. Furthermore, elevated HRAS seemed to promote resistance to EGFR inhibition because knockdown of HRAS in cells expressing constitutively active HRAS resulted in a significant reduction of IC50. CONCLUSIONS These findings confirm that increased HRAS expression is correlated with a lack of response to erlotinib in vivo while silencing of HRAS results in enhanced sensitivity to erlotinib in vitro. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e363-e364 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ian Udell Chapel Hill, NC More articles by this author Raj Kurpad Chapel Hill, NC More articles by this author Angela Smith Chapel Hill, NC More articles by this author Matthew Nielsen Chapel Hill, NC More articles by this author Raj Pruthi Chapel Hill, NC More articles by this author Eric Wallen Chapel Hill, NC More articles by this author Michael Woods Chapel Hill, NC More articles by this author William Kim Chapel Hill, NC More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...