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A New Technique for Treating Low-risk Prostate Cancer—Super Active Surveillance
Published on: November 7, 2025
ADT and activation of HGF and WNT axes in double-null prostate cancer
Dexter Hoi Long Leung1,2, Yao Mawulikplimi Adzavon1,2, Gaeul Chu1,2
1Department of Urology, New York University Grossman School of Medicine, New York, NY, USA.
Abstract:
Prostate cancer remains the most frequently diagnosed malignancy in men worldwide. Most primary prostate cancer cells express the androgen receptor (AR) and rely on androgens for oncogenic growth and progression. Thus, androgen deprivation therapy (ADT) that directly targets AR-expressing prostate cancer cells has been the frontline treatment for advanced prostate cancer. However, ADT inevitably fails in most patients, resulting in castration-resistant prostate cancer development. To inhibit reactivation of AR-promoted tumour progression via residual androgens and altered AR activation, next-generation AR antagonists and inhibitors of androgen biosynthesis were developed to improve clinical outcomes. However, these therapeutic advances also induce heterogeneous resistance phenotypes. Among them, double-null prostate cancer, featuring AR-null and neuroendocrine-null cell properties, occurs in patients treated with abiraterone and enzalutamide. Emerging clinical and experimental evidence demonstrates that current ADT induces HGF and canonical WNT signalling activation, which further elevates nuclear exporting and ribosomal biogenesis to foster tumour lineage plasticity and promote diverse castration-resistant prostate cancer phenotypes and double-null prostate cancer development. These mechanistic insights remain under active investigation, but they provide therapeutic prospects for co-targeting nuclear exporting, ribosomal biosynthesis and other oncogenic pathways in combination with current ADT to forestall the lethal disease.
Insights
Androgen deprivation therapy for prostate cancer can lead to resistance, including double-null prostate cancer. Targeting pathways like nuclear exporting and ribosomal biosynthesis may offer new treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Prostate cancer is a leading malignancy in men, often driven by the androgen receptor (AR).
- Androgen deprivation therapy (ADT) is a primary treatment, but resistance frequently develops, leading to castration-resistant prostate cancer (CRPC).
- Next-generation therapies face challenges with heterogeneous resistance, including double-null prostate cancer.
Purpose of the Study:
- To investigate mechanisms driving castration-resistant prostate cancer (CRPC) development under current therapies.
- To explore the role of HGF and WNT signaling in promoting tumor plasticity and resistance.
- To identify potential therapeutic targets for overcoming treatment resistance in advanced prostate cancer.
Main Methods:
- Analysis of clinical and experimental evidence on ADT resistance.
- Investigation of signaling pathways involved in CRPC, including HGF and WNT.
- Examination of molecular changes such as nuclear exporting and ribosomal biogenesis.
Main Results:
- ADT and advanced therapies can induce resistance phenotypes, including double-null prostate cancer.
- HGF and canonical WNT signaling activation are implicated in promoting CRPC.
- Elevated nuclear exporting and ribosomal biogenesis contribute to tumor lineage plasticity and resistance.
Conclusions:
- Understanding resistance mechanisms is crucial for improving prostate cancer treatment outcomes.
- Targeting nuclear exporting, ribosomal biosynthesis, and other oncogenic pathways alongside ADT shows therapeutic promise.
- Combined therapeutic strategies may help prevent the progression of lethal prostate cancer.
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