Presentation Abstract

Abstract Number: LB-59
Presentation Title: ERG induces taxane resistance in castration-resistant prostate cancer
Presentation Time: Sunday, Apr 07, 2013, 1:00 PM - 5:00 PM
Location: Hall A-E, Poster Section 48
Author Block: Giuseppe Galletti, Himisha Beltran, Alexandre Matov, Jacqueline Fontugne, Juan Miguel Mosquera, Ladan Fazli, Scott Tagawa, David Nanus, Martin Gleave, Mark Rubin, Paraskevi Giannakakou, David S. Rickman. Weill Cornell Medical College of Cornell Univ., New York, NY, University of British Columbia, Vancouver, BC, Canada
Abstract Body: Taxanes are the only chemotherapies to prolong survival for patients with metastatic castration-resistant prostate cancer (CRPC), and both docetaxel (doc) and cabazitaxel (cab) are FDA approved for this indication. Despite the initial efficacy of taxanes in treating CRPC, all patients ultimately fail due to the development of drug resistance. In this study we show that ERG over-expression, which occurs in roughly 50% of prostate cancers, is associated with both doc and cab resistance using in vitro and in vivo models of CRPC. Using either tetracycline-inducible or constitutively active expression systems in multiple prostate cancer cell lines, we found that ERG over-expression leads to at least a 10 fold increase in IC50 doses of doc or cab based on cell viability assays and inhibition of taxane-induced apoptosis. Similarly, ERG over-expressing prostate cancer xenografts were reproducibly more resistant to cab compared to the cab-sensitive control xenografts. Based on a biochemical and cell biological characterization, we observed that ERG binds directly to tubulin in the cytoplasm of prostate cancer cells, as well as in circulating tumor cells from patients treated with doc, and prevents taxane-induced microtubule stabilization. ERG over-expression affects several parameters of microtubule dynamics and inhibits effective drug-target engagement of doc or cab with tubulin, either directly via its tubulin interaction or indirectly by affecting transcription of genes that modulate microtubule homeostasis. In addition, ERG induces and binds to clusterin, a molecular chaperone also associated with taxane resistance. Clusterin knock-down with siRNA abrogates ERG-induced taxane resistance. Altogether, this data suggests that ERG, an oncogenic transcription factor, plays a novel role beyond regulating gene expression and functions outside the nucleus to cooperate with clusterin and tubulin in promoting taxane resistance. Determining ERG status in patient tumors may aid in patient selection for doc or cab therapy and/or influence co-targeting approaches using the clusterin antisense inhibitor OGX-011.