title: Acquired resistance to the second-generation androgen receptor antagonist enzalutamide in castration-resistant prostate cancer.
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.
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Kregel
authors.affiliation: Department of Biomedical Informatics and Internal Medicine, The Ohio State University, Columbus, OH, USA.
authors.forename: James L
authors.initials: JL
authors.lastname: Chen
authors.affiliation: Department of Surgery, Section of Urology, The University of Chicago, Chicago, IL, USA.
authors.forename: Westin
authors.initials: W
authors.lastname: Tom
authors.affiliation: Department of Surgery, Section of Urology, The University of Chicago, Chicago, IL, USA.
authors.forename: Venkatesh
authors.initials: V
authors.lastname: Krishnan
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Kach
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Hannah
authors.initials: H
authors.lastname: Brechka
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.
authors.forename: Tim B
authors.initials: TB
authors.lastname: Fessenden
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.|Department of Surgery, Section of Urology, The University of Chicago, Chicago, IL, USA.
authors.forename: Masis
authors.initials: M
authors.lastname: Isikbay
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL, USA.
authors.forename: Gladell P
authors.initials: GP
authors.lastname: Paner
authors.affiliation: Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA.
authors.forename: Russell Z
authors.initials: RZ
authors.lastname: Szmulewitz
authors.affiliation: Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA.|Department of Surgery, Section of Urology, The University of Chicago, Chicago, IL, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Vander Griend
mesh_terms: D059002:Androgen Receptor Antagonists / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000031:analogs & derivatives* / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: C410798:AR protein, human; D059002:Androgen Receptor Antagonists; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide
keywords: androgen receptor; castration-resistance; enzalutamide; prostate cancer