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<p>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&#xa0;(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,&#xa0;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 (<i>AXIN2</i>, <i>RNF43</i>, <i>ZNRF3</i>, <i>NKD1</i>) 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.</p>

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Role of the cross-regulation between Wnt pathway activation and androgen receptor signaling in prostate cancer treatment resistance

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月14日

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  • Nicolas Anselmino,
  • Pablo Sanchis,
  • Juan Bizzotto,
  • Estefania Labanca,
  • Jiabin Dong,
  • Peter D. A. Shepherd,
  • Jun Yang,
  • Elba S. Vazquez,
  • Joaquin Mateo,
  • Geraldine Gueron,
  • Christopher J. Logothetis

摘要

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.