Abstract
Enzalutamide (ENZ) is a potent androgen receptor (AR) antagonist with activity in castration-resistant prostate cancer (CRPC); however, progression to ENZ-resistant (ENZ-R) CRPC frequently occurs with rising serum PSA levels, implicating AR full-length (ARFL) or variants (AR-Vs) in disease progression. To define functional roles of ARFL and AR-Vs in ENZ-R CRPC, we designed 3 antisense oligonucleotides (ASO) targeting exon-1, intron-1, and exon-8 in AR pre-mRNA to knockdown ARFL alone or with AR-Vs, and examined their effects in three CRPC cell lines and patient-derived xenografts. ENZ-R-LNCaP cells express high levels of both ARFL and AR-V7 compared with CRPC-LNCaP; in particular, ARFL levels were approximately 12-fold higher than AR-V7. Both ARFL and AR-V7 are highly expressed in the nuclear fractions of ENZ-R-LNCaP cells even in the absence of exogenous androgens. In ENZ-R-LNCaP cells, knockdown of ARFL alone, or ARFL plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression, and delayed tumor growth in vivo. In 22Rv1 cells that are inherently ENZ-resistant, knockdown of both ARFL and AR-Vs more potently suppressed cell growth, AR transcriptional activity, and AR-regulated gene expression than knockdown of ARFL alone. Exon-1 AR-ASO also inhibited tumor growth of LTL-313BR patient-derived CRPC xenografts. These data identify the AR as an important driver of ENZ resistance, and while the contributions of ARFL and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both ARFL and AR-Vs is a rational approach for AR-dependent CRPC.
Highlights
First-line treatment for metastatic prostate cancer is androgen deprivation therapy (ADT), which reduces serum testosterone levels and androgen receptor (AR) activity
These data identify the AR as an important driver of ENZ resistance, and while the contributions of AR full-length (ARFL) and AR-Vs can vary across cell systems, ARFL is the key driver in the ENZ-R LNCaP model
ARFL and AR-V7 are highly expressed in ENZ-R cell lines and xenograft tissues
Summary
First-line treatment for metastatic prostate cancer is androgen deprivation therapy (ADT), which reduces serum testosterone levels and androgen receptor (AR) activity. Despite high initial response rates, remissions are temporary with emergence of castration-resistant prostate cancer (CRPC), largely driven by AR reactivation despite low levels of serum testosterone. Serum prostate-specific antigen (PSA) is an AR-regulated protein that. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).
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