期刊
ONCOTARGET
卷 7, 期 18, 页码 26259-26274出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.8456
关键词
androgen receptor; prostate cancer; castration-resistance; enzalutamide
资金
- University of Chicago Department of Surgery, the Section of Urology
- University of Chicago Comprehensive Cancer Center (UCCCC)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University [NCI P50 CA090386]
- Cancer Research Center of the University of Chicago
- American Cancer Society Institutional Research Grant (ACS-IRG) [IRG-58-004]
- Cancer Center Support Grant [P30 CA14599]
- Brinson Foundation
- Alvin Baum Family Fund
- Pierce Foundation
- University of Chicago Cancer Research Foundation Women's Board
- National Center for Advancing Translational Sciences of the National Institutes of Health [UL1 TR000430]
- DoD Award [W81XWH-14-1-0027]
- HHMI: Med-into-Grad Fellowship [56006772]
- Cancer Biology Training Grant [T32-CA09594]
- [RO1CA178431]
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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