Oncotarget

Research Papers:

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

Steven Kregel, James L. Chen, Westin Tom, Venkatesh Krishnan, Jacob Kach, Hannah Brechka, Tim B. Fessenden, Masis Isikbay, Gladell P. Paner, Russell Z. Szmulewitz and Donald J. Vander Griend _

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Oncotarget. 2016; 7:26259-26274. https://doi.org/10.18632/oncotarget.8456

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Abstract

Steven Kregel1, James L. Chen2, Westin Tom5, Venkatesh Krishnan5, Jacob Kach3, Hannah Brechka1, Tim B. Fessenden1, Masis Isikbay3,5, Gladell P. Paner4, Russell Z. Szmulewitz3,*, Donald J. Vander Griend1,5,*

1Committee on Cancer Biology, The University of Chicago, Chicago, IL, USA

2Department of Biomedical Informatics and Internal Medicine, The Ohio State University, Columbus, OH, USA

3Department of Medicine, Section of Hematology/Oncology, The University of Chicago, Chicago, IL, USA

4Department of Pathology, The University of Chicago, Chicago, IL, USA

5Department 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: [email protected]

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.


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