ARVib suppresses growth of advanced prostate cancer via inhibition of androgen receptor signaling
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jul 16, 2021
- Source ID
- 10.1038/s41388-021-01914-2
Entities
People
- Ai-Ming Yu
- Alan P. Lombard
- Allen C Gao
- Cameron M. Armstrong
- Chengfei Liu
- Christopher P Evans
- Chun-Yi Wu
- Clifford G Tepper
- Jinge Zhao
- Joy C. Yang
- Pui-kai Li
- Shu Ning
- Wei Lou
Organizations
- Engineer Research and Development Center
- National Cancer Institute
- United States Department of Veterans Affairs