RT Journal Article
SR Electronic
T1 Cross-resistance among next generation anti-androgen drugs through the AKR1C3/AR-V7 axis in advanced prostate cancer
JF Molecular Cancer Therapeutics
JO Mol Cancer Ther
FD American Association for Cancer Research
SP molcanther.0015.2020
DO 10.1158/1535-7163.MCT-20-0015
A1 Zhao, Jinge
A1 Ning, Shu
A1 Lou, Wei
A1 Yang, Joy C
A1 Armstrong, Cameron M.
A1 Lombard, Alan P.
A1 D'Abronzo, Leandro S
A1 Evans, Christopher P
A1 Gao, Allen C.
A1 Liu, Chengfei
YR 2020
UL http://mct.aacrjournals.org/content/early/2020/05/19/1535-7163.MCT-20-0015.abstract
AB The next generation anti-androgen drugs, XTANDI® (Enzalutamide), ZYTIGA® (Abiraterone acetate), ERLEADA™ (Apalutamide) and NUBEQA (Darolutamide) extend survival times and improve quality of life in advanced prostate cancer patients. Despite these advances, resistance occurs frequently and there is currently no definitive cure for Castration-Resistant Prostate Cancer (CRPC). Our previous studies identified that similar mechanisms of resistance to enzalutamide or abiraterone occur following treatment and cross-resistance exists between these therapies in advanced prostate cancer. Here we show that enzalutamide and abiraterone resistant prostate cancer cells are further cross-resistant to apalutamide and darolutamide. Mechanistically, we have determined that the AKR1C3/AR-V7 axis confers this cross-resistance. Knockdown of AR-V7 in enzalutamide resistant cells re-sensitize cells to apalutamide and darolutamide treatment. Furthermore, targeting AKR1C3 re-sensitizes resistant cells to apalutamide and darolutamide treatment through AR-V7 inhibition. Chronic apalutamide treatment in C4-2B cells activates the steroid hormone biosynthesis pathway and increases AKR1C3 expression which confers resistance to enzalutamide, abiraterone and darolutamide. In conclusion, our results suggest that apalutamide and darolutamide share similar resistant mechanisms with enzalutamide and abiraterone. The AKR1C3/AR-V7 complex confers cross-resistance to second generation AR-targeted therapies in advanced prostate cancer.