Prostate cancer has emerged as a significant global health concern, being the most frequently diagnosed malignancy among men. The reliance of primary prostate cancer cells on androgens for their growth and proliferation has established the androgen receptor (AR) as a critical target for therapeutic intervention. Androgen deprivation therapy (ADT) has long been the primary treatment modality for advanced stages of prostate cancer, specifically designed to target those AR-expressing cancer cells and inhibit their growth. However, resistance to this initial therapy is a common complication that leads to the development of castration-resistant prostate cancer (CRPC).
The transition from hormone-sensitive to castration-resistant disease is characterized by a complex reprogramming of the cancer cells, which can involve changes in their cellular architecture and signaling pathways. As a result, many patients undergoing ADT eventually experience a relapse in their condition. This resilience of the cancer cells brings to light the necessity of investigating additional therapeutic strategies to combat CRPC effectively. In recent years, the development of next-generation AR antagonists and agents that inhibit androgen biosynthesis has marked significant progress in this field, though the emergence of heterogeneous resistance mechanisms has complicated treatment outcomes.
Research has illuminated that even with advanced therapeutic agents, patients can still develop aggressive forms of prostate cancer, including those characterized by double-null phenotypes. This unique form of prostate cancer features both AR-null and neuroendocrine-null characteristics. Such phenotypes present substantial challenges in treatment, rendering conventional therapies suboptimal. Notably, these double-null prostate cancers have been observed in patients who have undergone treatment with agents such as abiraterone and enzalutamide, underscoring the need for a more comprehensive understanding of the underlying mechanisms that facilitate this resistance.
One of the pivotal insights into the mechanism of treatment failure lies in the activation of certain signaling pathways, specifically hepatocyte growth factor (HGF) and canonical WNT signaling. The activation of these pathways has been associated with the reactivation of AR-promoted tumor growth, occurring even when androgen levels are suppressed. This suggests that, despite ADT’s intent to starve cancer cells of their essential growth factors, compensatory biological networks can be upregulated, allowing the cancer to survive and thrive in a hormone-deprived environment.
Furthermore, the interplay between HGF and WNT signaling within the context of prostate cancer resilience indicates a complex regulatory landscape that fosters tumor lineage plasticity. This plasticity enables cancer cells to adapt quickly to therapeutic pressures, evolving into distinct and aggressive phenotypes that exhibit a varied resistance profile. As a result, understanding these molecular mechanisms not only provides essential insights into treatment resistance but also opens new avenues for innovative therapeutic strategies.
As researchers delve deeper into the molecular adaptations underpinning prostate cancer progression post-ADT, they have identified nuclear export mechanisms and ribosomal biogenesis as critical targets for intervention. These processes are intricately linked to the cancer cell’s ability to regulate protein synthesis and export key regulatory components, which are essential for their survival and proliferation. By co-targeting these pathways alongside conventional ADT, clinicians may be able to disrupt the cancer cell’s ability to adapt and overcome therapeutic constraints.
In this respect, the challenge lies not only in the discovery of new drugs but also in devising combination therapies that synergistically inhibit multiple pathways involved in prostate cancer biology. The idea is to harness the knowledge of signaling networks modulated by treatment to anticipate and mitigate potential resistance mechanisms before they emerge. Such an integrated therapeutic framework could significantly enhance patient outcomes and tackle the formidable burden of castration-resistant prostate cancer.
Therefore, as the landscape of prostate cancer treatment evolves, the importance of a multi-faceted approach becomes increasingly clear. By integrating findings on HGF and WNT signaling activation with the latest advancements in therapeutic technologies, researchers and clinicians are better positioned to develop effective management strategies for advanced prostate cancer. Future clinical trials will be critical in validating these approaches and in identifying biomarkers that can predict treatment response more reliably.
Crucially, ongoing research efforts into the cellular and molecular determinants of resistance are likely to illuminate further therapeutic targets. Innovations in precision medicine, which tailors treatment based on the unique genetic and molecular profile of a patient’s tumor, promise to revolutionize the management of prostate cancer. Ultimately, the goal remains not only to extend survival but also to improve the quality of life for patients battling this persistent malignancy.
These recent insights into the resistance mechanisms of prostate cancer highlight an urgent need for increased awareness and research funding dedicated to exploring these pathways. The development of clinically relevant models to study this transition, alongside a commitment to translating laboratory findings into clinical applications, will be vital in the ongoing fight against prostate cancer.
In conclusion, as we stand at the forefront of a new era in understanding prostate cancer biology, it is imperative that collaboration among researchers, oncologists, and patients continues to accelerate discoveries that can lead to effective new therapies. With sustained efforts and a collective commitment to overcoming the complexities of this disease, the future holds potential for significant advancements in the treatment and management of advanced prostate cancer.
Subject of Research: Prostate Cancer and Resistance Mechanisms to Androgen Deprivation Therapy
Article Title: ADT and activation of HGF and WNT axes in double-null prostate cancer
Article References:
Leung, D.H.L., Adzavon, Y.M., Chu, G. et al. ADT and activation of HGF and WNT axes in double-null prostate cancer.
Nat Rev Urol (2026). https://doi.org/10.1038/s41585-026-01129-8
Image Credits: AI Generated
DOI: 10.1038/s41585-026-01129-8
Keywords: Prostate Cancer, Androgen Receptor, Castration-Resistant Prostate Cancer, Androgen Deprivation Therapy, HGF Signaling, WNT Signaling, Therapeutic Resistance, Double-Null Phenotype, Ribosomal Biogenesis, Nuclear Export Mechanisms.
