Collateral resistance to taxanes in enzalutamide‐resistant prostate cancer through aberrant androgen receptor and its variants

• DOI: 10.1111/cas.13751
• Publication Date: 2018-07-27T07:54:31Z
• Authors: Masaki Shiota; Takashi Dejima; Yoshiaki Yamamoto; Ario Takeuchi; Kenjiro Imada; Eiji Kashiwagi; Junichi Inokuchi; Katsunori Tatsugami; Shunichi Kajioka; Takeshi Uchiumi; Masatoshi Eto
• Keywords: Male; Prostate; Original Articles; Prostate-Specific Antigen; Disease-Free Survival; 3. Good health; Prostatic Neoplasms, Castration-Resistant; 03 medical and health sciences; Treatment Outcome; 0302 clinical medicine; Drug Resistance, Neoplasm; Receptors, Androgen; Cell Line, Tumor; Gene Knockdown Techniques; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Nitriles; Phenylthiohydantoin; Androgen Receptor Antagonists; Humans; Taxoids; RNA, Small Interfering; Aged; Signal Transduction

Currently, the optimal sequential use of androgen receptor (AR) axis‐targeted agents and taxane chemotherapies remains undetermined. We aimed to elucidate the resistance status between taxanes and enzalutamide, and the functional role of the AR axis. Enzalutamide‐resistant 22Rv1 cells showed collateral resistance to taxanes, including docetaxel and cabazitaxel. However, taxane‐resistant cells showed no collateral resistance to enzalutamide; taxane‐resistant cells expressed comparable protein levels of full‐length AR and AR variants. Knockdown of both full‐length AR and AR variants rendered cells sensitive to taxanes, whereas knockdown of AR variants sensitized cells to enzalutamide, but not to taxanes. In contrast, overexpression of full‐length AR rendered cells resistant to taxanes. Consistently, the prostate‐specific antigen response and progression‐free survival in docetaxel chemotherapy were worse in cases with prior use of ARAT agents compared with cases without. Collateral resistance to taxanes was evident after obtaining enzalutamide resistance, and aberrant AR signaling might be involved in taxane resistance.