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.

Exploring the optimal sequence of abiraterone and enzalutamide in patients with chemotherapy‐naïve castration‐resistant prostate cancer: The Kyoto‐Baltimore collaboration

“…This might be one of the mechanisms explaining why ENZA was partially effective for ABI‐resistant CRPC patients. In contrast, the AR expression of ENZA‐resistant prostate cancer cell lines did not increase consistently, showing that non‐AR mediated mechanisms are mainly associated with treatment resistance . These mechanisms of resistance to ENZA could not be overcome by ABI.…”

PRKAR2B plays an oncogenic role in the castration-resistant prostate cancer

“…DU-145, PC-3 and 22RV1 are castration resistant prostate cancer cell lines and LNCaP is castration sensitive prostate cancer cell line which is sensitive to castration [10, 11]. Figure 2 showed that DU-145 and PC-3 has higher expression of PRKAR2B than22RV1 and LNCaP (Figure 2A and 2B).…”

Combined N‐terminal androgen receptor and autophagy inhibition increases the antitumor effect in enzalutamide sensitive and enzalutamide resistant prostate cancer cells

“…LNCaP (ATCC, CRL‐1740) and PC‐3 (CRL‐1435) cells were obtained from American Type Culture Collection (ATCC, Manassas, VA). In order to take account of the evolution of prostate cancer during androgen deprivation treatment, an established enzalutamide resistant cell line (LNCaP‐EnzR) was additionally used as a model of advanced CRPC . LNCaP‐EnzR cells were a generous gift from Dr. Donald J. Vander Griend (Urological Stem Cell Research, University of Chicago).…”

“…LNCaP‐EnzR cells were a generous gift from Dr. Donald J. Vander Griend (Urological Stem Cell Research, University of Chicago). The cells have been extensively described before . PNT1A epithelial cells were provided by Pirkko Härkönen (Institute of Biomedicine, University of Turku, Turku, Finland) .…”