Abstract Prostate cancer (PCa) is a biologically heterogeneous disease that frequently progresses to castration-resistant prostate cancer (CRPC), a challenging clinical stage. The underlying mechanisms driving CRPC progression and resistance to androgen receptor (AR) signaling inhibition (ARSI) remain incompletely understood. Emerging evidence implicates the canonical Wnt pathway as a key contributor to CRPC progression. This study elucidates the role of Wnt pathway activation in mediating resistance to ARSI and identifies a robust molecular signature for predicting treatment outcomes. By integrating genomic and transcriptomic data from PCa patients, patient-derived xenografts (PDXs), and experimental models harboring or not Wnt-activating mutations, we performed differential expression analysis, unsupervised clustering, survival, and viability analysis to assess Wnt/β-catenin pathway activation and its interaction with AR signaling. A specific Wnt transcriptional signature ( AXIN2 , RNF43 , ZNRF3 , NKD1 ) was found to reliably reflect pathway activation in advanced PCa. AR was found to suppress mutation-driven Wnt signaling, which was upregulated upon AR inhibition, contributing to treatment resistance. Targeting β-catenin interactions with co-activators p300/CBP using selective inhibitors (IQ-1 and ICG-001) effectively mitigated Wnt-driven ARSI resistance, restoring sensitivity to therapy in preclinical models. Thus, canonical Wnt pathway activation emerges as a critical mediator of resistance to ARSI in CRPC. The identified Wnt signature holds potential as a biomarker for predicting and monitoring therapeutic outcomes. Concurrent targeting of AR and Wnt signaling represents a promising strategy to overcome treatment resistance, particularly in patients with Wnt-activating mutations.
Anselmino et al. (2026) studied this question.