Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer

// Steven Kregel 1 , James L. Chen 2 , Westin Tom 5 , Venkatesh Krishnan 5 , Jacob Kach 3 , Hannah Brechka 1 , Tim B. Fessenden 1 , Masis Isikbay 3, 5 , Gladell P. Paner 4 , Russell Z. Szmulewitz 3, * , Donald J. Vander Griend 1, 5, * 1 Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA 2 Department of Biomedical Informatics and Internal Medicine, The Ohio State University, Columbus, OH, USA 3 Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA 4 Department of Pathology, The University of Chicago, Chicago, IL, USA 5 Department of Surgery, Section of Urology, The University of Chicago, Chicago, IL, USA * These authors contributed equally to this work Correspondence to: Donald J. Vander Griend, email: prostate@uchicago.edu Keywords: androgen receptor, prostate cancer, castration-resistance, enzalutamide Received: October 06, 2015      Accepted: March 13, 2016      Published: March 29, 2016 ABSTRACT Enzalutamide (MDV3100) is a second generation Androgen Receptor (AR) antagonist with proven efficacy in the treatment of castration resistant prostate cancer (CRPC). The majority of treated patients, however, develop resistance and disease progression and there is a critical need to identify novel targetable pathways mediating resistance. The purpose of this study was to develop and extensively characterize a series of enzalutamide-resistant prostate cancer cell lines. Four genetically distinct AR-positive and AR-pathway dependent prostate cancer cell lines (CWR-R1, LAPC-4, LNCaP, VCaP) were made resistant to enzalutamide by long-term culture (> 6 months) in enzalutamide. Extensive characterization of these lines documented divergent in vitro growth characteristics and AR pathway modulation. Enzalutamide-resistant LNCaP and CWR-R1 cells, but not LAPC-4 and VCAP cells, demonstrated increased castration-resistant and metastatic growth in vivo . Global gene expression analyses between short-term enzalutamide treated vs. enzalutamide-resistant cells identified both AR pathway and non-AR pathway associated changes that were restored upon acquisition of enzalutamide resistance. Further analyses revealed very few common gene expression changes between the four resistant cell lines. Thus, while AR-mediated pathways contribute in part to enzalutamide resistance, an unbiased approach across several cell lines demonstrates a greater contribution toward resistance via pleiotropic, non-AR mediated mechanisms.