TY - JOUR
T1 - Collateral resistance to taxanes in enzalutamide-resistant prostate cancer through aberrant androgen receptor and its variants
AU - Shiota, Masaki
AU - Dejima, Takashi
AU - Yamamoto, Yoshiaki
AU - takeuchi, ario
AU - Imada, Kenjiro
AU - Kashiwagi, Eiji
AU - Inokuchi, Junichi
AU - Tatsugami, Katsunori
AU - Kajioka, Shunichi
AU - Uchiumi, Takeshi
AU - Eto, Masatoshi
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant no. 17K11145), a Medical Research Promotion Grant from Takeda Science Foundation, and a Research Promotion Grant from Shin‐Nihon Foundation of Advanced Medical Research. We are grateful to Dr. Toshihiko Yanase (Fukuoka University, Fukuoka, Japan) for providing the AR‐GFP expression plasmid. We would like to thank Ms. Noriko Hakoda and Ms. Eriko Gunshima for technical assistance, and Edanz Group Japan for editorial assistance.
Funding Information:
This work was supported by the Japan Society for the Promotion of Science KAKENHI (grant no. 17K11145), a Medical Research Promotion Grant from Takeda Science Foundation, and a Research Promotion Grant from Shin-Nihon Foundation of Advanced Medical Research. We are grateful to Dr. Toshihiko Yanase (Fukuoka University, Fukuoka, Japan) for providing the AR-GFP expression plasmid. We would like to thank Ms. Noriko Hakoda and Ms. Eriko Gunshima for technical assistance, and Edanz Group Japan for editorial assistance.
Publisher Copyright:
© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
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U2 - 10.1111/cas.13751
DO - 10.1111/cas.13751
M3 - Article
C2 - 30051622
AN - SCOPUS:85052793434
SN - 1347-9032
VL - 109
SP - 3224
EP - 3234
JO - Cancer Science
JF - Cancer Science
IS - 10
ER -
