**1. Introduction**

The primary effective treatment for most recurring prostate cancer (PC) is androgen deprivation therapy (ADT). Although initially effective, the malignancy will eventually form castration-resistant prostate cancer (CRPC) [1]. Current treatment options for CRPC are androgen receptor- (AR-) targeted therapies, such as enzalutamide and abiraterone, as well as taxanes, such as docetaxel and cabazitaxel. However, no curative CRPC therapy is available for the presentation of treatment resistance [2]. The mechanisms of CRPC development include overexpression of AR [3,4], gain-of-function mutations in the AR ligand-binding domain (LBD) [5], intratumoral androgen synthesis [6], altered expression and function of the AR coactivators [7,8], aberrant post-translational modification of the AR [9], and the AR splice variants (AR-Vs) lacking the LBD [10]. Expression of AR-V7 in human prostate cancer cell lines mediates resistance to enzalutamide and abiraterone [11,12]. EPI compounds are AR amino-terminal

domain- (NTD-) targeting drugs that block the transcriptional activities of full-length (FL)-AR and AR-Vs in vitro and exhibit antitumor activity in CRPC xenografts [13–15]. Resistance to taxane-based chemotherapy is frequently attributed to the overexpression of the transporter protein, P-glycoprotein (P-gp), which is also known as ATP-binding cassette subfamily B member 1 (ABCB1) or multidrug resistance protein 1 (MDR-1) [16,17]. Prostate cancer specimens from CRPC patients have increased levels of P-gp [18]. Cabazitaxel is highly cytotoxic with a low affinity for P-gp [19], and therefore, it is not considered to be clinically cross-resistant with docetaxel, thereby providing a survival benefit for docetaxel-pretreated patients [20]. However, a recent report indicated that P-gp could mediate cabazitaxel–docetaxel cross-resistance in advanced prostate cancer [21]. Alternative mechanisms of resistance to taxanes may involve tubulin mutations [22], although the precise association has ye<sup>t</sup> to be elucidated. The presence of AR-V7 in circulating tumor cells from men with metastatic CRPC is not associated with primary resistance to taxane chemotherapy [23,24], which is contrary to pre-clinical data suggesting that the expression of AR-V7 mediates resistance to docetaxel in LuCap23.1 human prostate cancer xenografts [25]. In this study, we focused specifically on the role of AR-V7 in taxane resistance in pre-clinical models of prostate cancer to address this clinically important question. We employed the CRPC cell line, LNCaP95, which endogenously expresses AR-V7, to examine the status of cross-resistance between docetaxel and cabazitaxel, and to assess the involvement of AR-V7 with taxane resistance. We further evaluated the effect of EPI-002, an NTD-targeting drug, on enzalutamide resistant LNCaP95 cells with acquired resistance to taxanes.
