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Published on: October 24, 2019
Androgen receptor degraders overcome common resistance mechanisms developed during prostate cancer treatment
Steven Kregel1, Chao Wang2, Xin Han2
1Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI 48109, USA; Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
Abstract:
Androgen receptor (AR) antagonists, such as enzalutamide, have had a major impact on the treatment of metastatic castration-resistant prostate cancer (CRPC). However, even with the advent of AR antagonist therapies, patients continue to develop resistance, and new strategies to combat continued AR signalling are needed. Here, we develop AR degraders using PROteolysis TArgeting Chimeric (PROTAC) technology in order to determine whether depletion of AR protein can overcome mechanisms of resistance commonly associated with current AR-targeting therapies. ARD-61 is the most potent of the AR degraders and effectively induces on-target AR degradation with a mechanism consistent with the PROTAC design. Compared to clinically-approved AR antagonists, administration of ARD-61 in vitro and in vivo results in more potent anti-proliferative, pro-apoptotic effects and attenuation of downstream AR target gene expression in prostate cancer cells. Importantly, we demonstrate that ARD-61 functions in enzalutamide-resistant model systems, characterized by diverse proposed mechanisms of resistance that include AR amplification/overexpression, AR mutation, and expression of AR splice variants, such as AR-V7. While AR degraders are unable to bind and degrade AR-V7, they continue to inhibit tumor cell growth in models overexpressing AR-V7. To further explore this, we developed several isogenic prostate cell line models in which AR-V7 is highly expressed, which also failed to influence the cell inhibitory effects of AR degraders, suggesting that AR-V7 is not a functional resistance mechanism for AR antagonism. These data provide compelling evidence that full-length AR remains a prominent oncogenic driver of prostate cancers which have developed resistance to AR antagonists and highlight the clinical potential of AR degraders for treatment of CRPC.
Insights
New PROTAC technology creates androgen receptor (AR) degraders that overcome resistance to current prostate cancer therapies. These AR degraders show potent anti-cancer effects, offering new hope for metastatic castration-resistant prostate cancer (CRPC) treatment.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- Metastatic castration-resistant prostate cancer (CRPC) remains a challenge despite androgen receptor (AR) antagonist therapies like enzalutamide.
- Therapeutic resistance to AR antagonists is a significant clinical problem, necessitating novel treatment strategies.
- Continued AR signaling drives tumor progression even in resistant CRPC cases.
Purpose of the Study:
- To develop novel androgen receptor (AR) degraders using PROteolysis TArgeting Chimeric (PROTAC) technology.
- To investigate if AR protein depletion can overcome resistance mechanisms to current AR-targeting therapies.
- To evaluate the efficacy of AR degraders in preclinical models of CRPC, including those resistant to enzalutamide.
Main Methods:
- Development and characterization of AR degraders, specifically ARD-61, utilizing PROTAC technology.
- In vitro and in vivo testing of ARD-61 in prostate cancer cell lines and xenograft models.
- Assessment of AR degradation, anti-proliferative effects, apoptosis induction, and downstream target gene expression.
- Evaluation of AR degrader efficacy in enzalutamide-resistant models with known resistance mechanisms (AR amplification, mutation, AR-V7).
Main Results:
- ARD-61 demonstrated potent, on-target AR degradation via PROTAC mechanism.
- ARD-61 exhibited superior anti-proliferative and pro-apoptotic effects compared to enzalutamide in vitro and in vivo.
- ARD-61 effectively inhibited tumor growth in enzalutamide-resistant models, including those with AR amplification, mutation, and AR-V7 expression.
- While AR degraders do not degrade AR-V7, they remain effective against AR-V7 expressing cells, indicating AR-V7 is not a primary resistance driver.
Conclusions:
- Full-length AR remains a critical oncogenic driver in enzalutamide-resistant prostate cancer.
- AR degraders, exemplified by ARD-61, represent a promising therapeutic strategy for overcoming resistance in CRPC.
- PROTAC technology offers a viable approach to target AR signaling and improve treatment outcomes for advanced prostate cancer.
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