What is the pathophysiologic mechanism for developing castrate-resistant prostate cancer (CRPC) in older males with a history of prostate cancer treated with androgen deprivation therapy (ADT)?

Pathophysiologic Mechanisms of Castration-Resistant Prostate Cancer

Castration-resistant prostate cancer develops primarily through continued androgen receptor (AR) activation despite castrate testosterone levels, not through true androgen independence. 1

Core Mechanism: Persistent AR Signaling

The fundamental pathophysiology centers on the androgen receptor remaining active despite androgen deprivation therapy. 1 This occurs through several direct AR-dependent mechanisms:

AR Gene Alterations

• AR gene amplification allows increased receptor expression, enabling cells to respond to minimal androgen levels 2
• Gain-of-function mutations in the AR gene create receptors that respond to non-androgenic steroids or remain constitutively active 2
• AR splice variants (particularly AR-V7) produce truncated receptors lacking the ligand-binding domain, resulting in constitutive activation independent of androgens 2

Intratumoral Androgen Production

• Adrenal-derived androgen precursors (DHEA, androstenedione) are converted to potent androgens within the tumor microenvironment 3
• Upregulation of steroidogenic enzymes (CYP17A1, AKR1C3, HSD3B1) enables local synthesis of dihydrotestosterone (DHT) from circulating precursors 3
• 11-oxygenated androgens represent an alternative pathway to produce AR-activating steroids that bypass traditional androgen synthesis routes 3

AR Transcriptional Regulation

• Altered coactivator/corepressor ratios shift the balance toward enhanced AR transcriptional activity even with minimal ligand binding 2
• Post-translational modifications of AR protein affect its stability, nuclear localization, and transcriptional activity 2

Secondary AR-Independent Pathways

While AR signaling dominates, ancillary mechanisms contribute to castration resistance:

Growth Factor Signaling

• RAS/MAPK pathway activation provides survival signals that bypass androgen dependence 2
• PI3K/AKT pathway upregulation promotes cell survival and proliferation independent of AR 2
• FGF signaling creates alternative growth pathways 2

Stem Cell and Lineage Plasticity

• AR downregulation or loss occurs in a significant subset of CRPC cases, representing true AR-independent disease 4
• Neuroendocrine differentiation transforms adenocarcinoma cells into AR-negative, treatment-resistant neuroendocrine cells 4
• AR-low/negative subtypes represent approximately 15-30% of CRPC cases and do not respond to AR-targeted therapies 4

Microenvironment Interactions

• JAK/STAT pathway activation through cytokine signaling promotes castration resistance 2
• Wnt/β-catenin signaling supports stem-like properties and treatment resistance 2
• TGF-β/SMAD pathway modulates epithelial-mesenchymal transition and metastatic potential 2

Clinical Implications

The disease remains androgen-dependent in most cases despite castrate serum testosterone, which is why ADT must be continued indefinitely even after progression to CRPC. 1, 5 This understanding led to development of second-generation AR inhibitors (enzalutamide, apalutamide, darolutamide) and androgen synthesis inhibitors (abiraterone) that target these persistent AR signaling mechanisms. 6

Critical Pitfall

The term "castration-resistant" is misleading—it does not mean androgen-independent. 1 Some disease may be inherently resistant at presentation, but the majority develops resistance through adaptive mechanisms that maintain AR signaling through alternative routes. 1, 6 Recognizing AR-low/negative subtypes is essential, as these patients require different therapeutic approaches beyond AR-targeted agents. 4