Recently, the research group led by Dr. Dechao Feng, Lecturer at University College London (UCL) and Distinguished Research Fellow at Zhejiang Provincial People’s Hospital, published a review entitled “Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer”. Aligned with the paradigm shift toward precision medicine and individualized management in prostate cancer, this review systematically summarizes the adaptive changes in intratumoral androgen metabolism and androgen receptor (AR) signaling during disease progression from hormone-sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC) and the highly aggressive subtypes (DNPC and NEPC) emerging during castration resistance, along with research advances in how these mechanisms contribute to therapy resistance. Furthermore, the review critically analyzes current challenges in studying prostate cancer resistance, and outlines future directions toward high-throughput, refined, and personalized strategies, emphasizing the integration of multi-omics technologies and novel in vitro and in vivo models to advance mechanistic insights into drug resistance, thereby establishing a scientific foundation for optimizing individualized therapeutic approaches.
Citation: Ye J, Xie Y, Wang J, Wu R, Li D, Yoo KH, Wusiman D, Cho WC, Lyu Z, Feng D. Intratumoral Androgens and Genetic Variants Driving Therapy Resistance in Prostate Cancer. Research 2026;9:Article 1128. https://doi.org/10.34133/ research.1128.
Background
Prostate cancer is a highly prevalent malignancy among men worldwide, and its disease burden continues to rise with the accelerating aging of the population, posing an increasingly serious threat to global male health. Currently, androgen deprivation therapy (ADT) combined with androgen receptor signaling inhibitors (ARSIs) represents the first-line treatment for advanced prostate cancer, effectively delaying disease progression by suppressing androgen synthesis and androgen receptor (AR) signaling. However, despite initial responsiveness to endocrine therapy, most patients inevitably develop castration-resistant prostate cancer (CRPC), which may further progress to the more aggressive subtypes of double-negative prostate cancer (DNPC) and neuroendocrine prostate cancer (NEPC). Throughout this process, adaptive changes in androgens and the AR signaling pathway—including sustained intratumoral androgen synthesis, AR gene amplification and mutation, emergence of AR splice variants, and activation of bypass signaling pathways—play a critical role in driving treatment resistance and disease progression.
Metabolic Reprogramming of Intratumoral Androgen Synthesis
Under normal conditions, over 90% of androgens are secreted by the testes. In the low-circulating-androgen environment induced by ADT, prostate cancer tissues maintain intratumoral androgen levels through metabolic reprogramming. This is achieved primarily via the utilization of adrenal-derived precursors—such as dehydroepiandrosterone sulfate (DHEAS), androstenedione (AED), and 11β-hydroxyandrostenedione (11OHA4)—as well as through de novo synthesis within the local tumor tissue. These substrates are converted into active androgens, including testosterone and dihydrotestosterone, via the classical pathway, backdoor pathway, 5α-dione pathway, and 11OHA4 pathway (Figure 1). Among these, the 5α-dione pathway plays a critical role due to its high metabolic efficiency, while the 11OHA4 pathway generates 11-oxygenated androgens (11-KT and 11-KDHT) that exhibit potent AR activating capacity and are resistant to inactivation by glucuronidation. The reprogramming of these intratumoral androgen synthesis pathways under therapeutic pressure represents a key mechanism driving resistance to ARSIs, including abiraterone.
Adaptive Remodeling and Interaction Network of the AR Pathway under Endocrine Therapy Pressure
In the AR signaling pathway, androgen binding to the ligand-binding domain (LBD) induces dissociation from heat shock proteins, conformational changes, and subsequent nuclear translocation, where AR binds to androgen response elements and regulates the transcription of genes involved in cell proliferation, senescence, and prostate function (like MYC, H2AJ, KLK2/3). Under the therapeutic pressure of ADT and ARSIs, the AR pathway undergoes multifaceted remodeling that drives treatment resistance (Figure 2). As endocrine therapy pressure persists, AR signaling is sustained through non-canonical mechanisms: upregulation of AR expression enhances sensitivity to low concentrations of androgens; LBD point mutations alter LBD conformation and can convert antagonists into agonists; and AR splice variants (like AR-V7), which lack the LBD while retaining the N-terminal domain (NTD) and DNA-binding domain, exhibit androgen-independent activation. In parallel, the AR pathway engages in complex bidirectional crosstalk with key signaling networks, including PI3K/AKT, WNT/β-catenin, and NF-κB. Additionally, growth factors and cytokines can mediate AR phosphorylation via downstream kinases, activating AR transcriptional activity under androgen-independent conditions. Collectively, this AR-centric molecular remodeling and its intricate crosstalk with multiple critical signaling pathways form the complex mechanistic foundation underlying endocrine therapy resistance in prostate cancer.
Lineage Evolution and AR Spatiotemporal Heterogeneity in Prostate Cancer under Endocrine Pressure
Under sustained therapeutic pressure from endocrine therapy, prostate cancer gradually progresses from hormone-sensitive prostate cancer (HSPC) to CRPC, and further evolves into AR-independent, highly aggressive subtypes such as DNPC and NEPC (Figure 3). Spatially, primary prostate tumors are predominantly composed of AR⁺ cells but contain AR⁻/lo subpopulations, whereas metastatic lesions may exhibit both hyperactivated AR signaling and AR⁻/lo phenotypes. Moreover, multiple genomic aberrations related to AR signaling can coexist across distinct metastatic sites. Temporally, endocrine therapy reshapes the AR pathway through a dual mechanism of “selection” and “induction”. While eliminating hormone-sensitive AR⁺ subpopulations, therapeutic pressure drives adaptive changes in AR⁺ tumor cells—including AR amplification, mutations, and activation of non-canonical pathways—ultimately contributing to the heterogeneity of CRPC. Additionally, key genetic deficiencies such as TP53/RB1 loss and KMT2C deficiency promote the loss of AR expression and classical adenocarcinoma features, driving tumor cells toward highly aggressive subtypes (NEPC and DNPC). This lineage plasticity leads to resistance to endocrine therapy and is associated with poor clinical outcomes.
Future Directions
The AR signaling axis plays a critical role in prostate cancer progression and therapeutic resistance. Accordingly, therapeutic development should focus on the androgen metabolic/AR signaling axis to establish synergistic strategies that effectively overcome resistance by targeting both AR pathway activity and its alternative routes. Prostate cancer is a highly heterogeneous disease, yet traditional research approaches often rely on static samples, which fail to capture real-time tumor evolution under therapeutic pressure. This limitation, coupled with a lack of reliable resistance biomarkers, poses a critical bottleneck for clinical translation. To address spatiotemporal heterogeneity, future research should integrate longitudinal samples, liquid biopsies, and organoid models with single-cell and spatial multi-omics technologies to enable dynamic monitoring and precision intervention in resistance evolution, thereby facilitating the transition from conventional homogenized treatment to a fully individualized, whole-course management paradigm. Lineage plasticity represents a key driver of prostate cancer resistance and progression; therefore, future efforts must focus on elucidating the critical determinants driving lineage transformation to overcome resistance barriers and improve patient outcomes.
The complete study is accessible via DOI:0.34133/research.1128