Abstract
Targeting androgen signaling with the second-generation anti-androgen drugs, such as enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro), is the mainstay for the treatment of castration-resistant prostate cancer (CRPC). While these treatments are effective initially, resistance occurs frequently. Continued expression of androgen receptor (AR) and its variants such as AR-V7 despite AR-targeted therapy contributes to treatment resistance and cancer progression in advanced CRPC patients. This highlights the need for new strategies blocking continued AR signaling. Here, we identify a novel AR/AR-V7 degrader (ARVib) and found that ARVib effectively degrades AR/AR-V7 protein and attenuates AR/AR-V7 downstream target gene expression in prostate cancer cells. Mechanistically, ARVib degrades AR/AR-V7 protein through the ubiquitin-proteasome pathway mediated by HSP70/STUB1 machinery modulation. ARVib suppresses HSP70 expression and promotes STUB1 nuclear translocation, where STUB1 binds to AR/AR-V7 and promotes its ubiquitination and degradation. ARVib significantly inhibits resistant prostate tumor growth and improves enzalutamide treatment in vitro and in vivo. These data suggest that ARVib has potential for development as an AR/AR-V7 degrader to treat resistant CRPC.
Highlights
Targeting androgen signaling via androgen deprivation therapy (ADT) is the first line treatment for prostate cancer (PCa)
In the present study, we identified a new androgen receptor (AR)/AR-variant 7 (AR-V7) degrader called ARVib from a library of synthetic analogs of niclosamide, which was previously identified as a potent inhibitor of AR and ARV7
We demonstrate that ARVib has better bioavailability and PK parameters than niclosamide, and can effectively degrade AR/ARV7 and attenuate AR/AR-V7 downstream target gene expression in prostate cancer cells
Summary
Targeting androgen signaling via androgen deprivation therapy (ADT) is the first line treatment for prostate cancer (PCa). The majority of men eventually develop castration-resistant prostate cancer (CRPC). Enzalutamide (Enza), abiraterone (Abi), apalutamide (Apal), and darolutamide (Daro) are the second-generation anti-androgen drugs used for the treatment of CRPC and function by inhibiting androgen receptor (AR) signaling [1,2,3,4]. Even though Enza and Abi have been shown to be effective initially, resistance to Enza and Abi occurs frequently. Considerable evidence from both clinical and experimental studies demonstrates that expression of AR-variant 7 (AR-V7) plays a vital role in promoting CRPC progression and induction of resistance to Enza and Abi therapy [5,6,7]. There is an urgent need to develop novel agents and strategies to block AR/AR-V7 to overcome resistance
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