Abstract

<div>Abstract<p><b>Purpose:</b> 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 (AR<sub>FL</sub>) or variants (AR-Vs) in disease progression.</p><p><b>Experimental Design:</b> To define functional roles of AR<sub>FL</sub> 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 AR<sub>FL</sub> alone or with AR-Vs, and examined their effects in three CRPC cell lines and patient-derived xenografts.</p><p><b>Results:</b> ENZ-R-LNCaP cells express high levels of both AR<sub>FL</sub> and AR-V7 compared with CRPC-LNCaP; in particular, AR<sub>FL</sub> levels were approximately 12-fold higher than AR-V7. Both AR<sub>FL</sub> 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 AR<sub>FL</sub> alone, or AR<sub>FL</sub> plus AR-Vs, similarly induced apoptosis, suppressed cell growth and AR-regulated gene expression, and delayed tumor growth <i>in vivo</i>. In 22Rv1 cells that are inherently ENZ-resistant, knockdown of both AR<sub>FL</sub> and AR-Vs more potently suppressed cell growth, AR transcriptional activity, and AR-regulated gene expression than knockdown of AR<sub>FL</sub> alone. Exon-1 AR-ASO also inhibited tumor growth of LTL-313BR patient-derived CRPC xenografts.</p><p><b>Conclusions:</b> These data identify the AR as an important driver of ENZ resistance, and while the contributions of AR<sub>FL</sub> and AR-Vs can vary across cell systems, AR<sub>FL</sub> is the key driver in the ENZ-R LNCaP model. AR targeting strategies against both AR<sub>FL</sub> and AR-Vs is a rational approach for AR-dependent CRPC. <i>Clin Cancer Res; 21(7); 1675–87. ©2015 AACR</i>.</p></div>

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