Abstract 399: Targeted protein degradation of the androgen receptor by ARCC-4 and ARD-2128: proteomic and therapeutic potential in AR-driven cancers

Background: The androgen receptor (AR) plays a central role in the progression of prostate cancer, where AR signaling drives tumor cell growth and survival. Current treatment strategies, including androgen deprivation therapy and AR antagonists like enzalutamide, aim to reduce AR activation. However, resistance often develops partly due to compensatory upregulation of the AR protein. Targeted protein degradation (TPD) represents an alternative strategy to overcome the limitations of traditional therapies by degrading the AR protein rather than merely inhibiting its function. Methods: This study investigated the AR-targeting degraders, ARCC-4 and ARD-2128, and their effects on AR nuclear translocation and transactivation in AR-expressed CHO-K1 cells. Additionally, in vitro efficacy was evaluated in cell proliferation assays, notably using the LNCaP clone FGC prostate cancer cell line. Proteomic analysis was conducted to examine global protein profiles and signaling pathways impacted by each degrader. Results: ARCC-4 and ARD-2128, which act via distinct E3 ligase pathways (VHL and CRBN, respectively), demonstrated significant AR degradation, with ARD-2128 achieving greater potency in reducing AR nuclear translocation and transactivation. Both degraders showed lower GI50 values and greater efficacy in suppressing cell proliferation in LNCaP clone FGC cells when compared with enzalutamide. Additionally, proteomic analysis highlighted distinct molecular signatures associated with each degrader, revealing differential effects on AR network proteins and broader signaling pathways. Conclusion: The potent growth inhibition observed with ARCC-4 and ARD-2128, as compared with enzalutamide, underscores the therapeutic potential of TPD in AR-driven cancers. These findings also potentially support TPD as a robust approach for overcoming resistance mechanisms associated with AR-targeted therapies. Broader profiling using the OncoPanel® platform would further demonstrate the therapeutic potential and selectivity of AR degraders such as ARCC-4 and ARD-2128. Investigation in additional prostate and breast cancer cell lines with diverse nuclear hormone receptor expression would be particularly relevant and may offer insights into the application of AR-targeted degradation across different cancer types, potentially leading to more effective treatment options. Citation Format: Elsa Liu, Judy Fu, Lori Fan, Luciano Galdieri, Justin Lipner, Steven Garner, Brogan Epkins, Emily Schultz, Daria Clucas, Kaitlyne Powers, Julie Chung, Ian Huang, Pei Ching Cheng, Phil Lin, Alastair J. King, ChunYao Lee. Targeted protein degradation of the androgen receptor by ARCC-4 and ARD-2128: proteomic and therapeutic potential in AR-driven cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 399.