Molecular mechanisms and classification of castration-resistant prostate cancer: Insights into androgen receptor, cancer stem cells, and neuroendocrine features

Abstract

Castration-resistant prostate cancer (CRPC) is a considerable clinical challenge, driven by complex molecular mechanisms that enable tumors to evade androgen deprivation therapy. This review explores the molecular mechanisms driving CRPC progression, focusing on androgen receptor (AR) signaling, cancer stem cells (CSCs), and neuroendocrine differentiation (NED). In AR-dependent CRPC, AR signaling remains pivotal in disease progression. Mutations, splice variants, alternative pathways, and transcriptional regulation facilitate sustained AR activation despite androgen deprivation therapy. In addition, CSCs promote tumor recurrence and treatment resistance by maintaining cellular heterogeneity and evading conventional therapies. Furthermore, castration-resistant neuroendocrine prostate cancer, an aggressive subtype of CRPC, is characterized by AR independence and NED, making treatment challenging. These findings underscore the need for therapeutic strategies targeting AR-, CSC-, and NED-specific mechanisms. Crucially, the molecular classification of CRPC into AR-dependent CRPC, stem cell-like CRPC, and castration-resistant neuroendocrine prostate cancer subtypes—based on the interplay between AR signaling, CSCs, and neuroendocrine features—is essential for advancing precision medicine. Tailoring treatments to the molecular subtype and characteristics of each patient offers the potential to substantially improve prognosis and survival in CRPC.

Keywords

Castration-resistant prostate cancer / Androgen receptor signaling / Cancer stem cell / Neuroendocrine prostate cancer / Biomarker / Molecular subtype

Acknowledgments

The figures were created using the Biorender.com (www.biorender.com).

Statement of ethics

Not applicable.

Conflict of interest statement

YN is an Associate Editor; YW is a member of Editorial board; JY is a member of Early Career Editorial Board of Current Urology. They confirm no involvement in any stage of this article’s review process, ensuring unbiased editorial decision-making. No conflict of interest has been declared by the other authors.

Funding source

This work was supported by the National Natural Science Foundation of China (Grant Number 82273262; 81872078), the Tianjin Health Science and Technology Project (Grant number TJWJ2024XK007), the Natural Science Foundation of Tianjin (Grant Number 21JCYBJC01430), Key Program of Tianjin Municipal Education Commission (Grant Number 2022ZD071), Tianjin Health Research Project (Grant Number TJWJ2023MS006), Tianjin Institute of Urology Funding Program (Grant Number MYSRC202315), Tianjin Health Research Project (Grant Number TJWJ2023XK008), and Scientific Research Program of Tianjin Municipal Education Commission (Grant Number 2023KJ022).

Author contributions

YS, ZL, JM, YF: Conceptualization, methodology, investigation, and writing-original draft preparation;

JY, HH, YL: Investigation, methodology, and writing-review and editing;

YW, YN: Funding acquisition, supervision.

Data availability

Data sharing is not applicable to this article, as no datasets were generated or analyzed in the current study.

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