Targeting Androgen Receptor Resistance in Prostate Cancer: The Role of Degraders

The study focuses on the role of androgen receptor (AR) signaling in prostate cancer (PCa) and the development of resistance to AR-targeted therapies like enzalutamide. Researchers hypothesized that AR protein remains active even in resistant states and utilized the proteolysis targeting chimera (PROTAC) strategy to create ARD-61, a compound that induces proteasomal degradation of AR. The molecule was designed to target AR in enzalutamide-resistant and AR splice variant overexpressing cells both in vitro and in vivo.

To assess ARD-61, various methods were employed, including western blotting, qRT-PCR, growth assays, xenograft studies, proteomic, and RNA-sequencing analyses. The sensitivity of different AR variants to ARD-61 was investigated by creating stable AR-V7 overexpression in LNCaP cells using CRISPR-Cas9. The results showed that ARD-61 rapidly and specifically degrades AR protein, reducing downstream AR signaling across various AR-positive cell lines and tumor xenografts. Both enzalutamide-sensitive and -resistant cell lines were found to be equally responsive to ARD-61.

The study concludes that full-length AR is essential throughout all stages of PCa. Even in the presence of enzalutamide, resistant cell lines depend on full-length AR for survival. Additionally, AR-variant overexpression, which is known to contribute to resistance to AR-targeted therapies, still requires an intact ligand-binding domain of the AR protein to sustain growth. The findings underscore the significance of persistent AR targeting in advanced PCa and demonstrate the potential of ARD-61 as an effective therapeutic agent. The researchers anticipate that the clinical application of ARD-61 will represent a significant advancement in the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC).

The research was presented by Steven Kregel et al. at the Annual Meeting of the American Association for Cancer Research in 2020.