Comparative Analysis of Castration-Resistant Prostate Cancer Subtypes: Identification of MEK Signaling as Therapeutic Target in Double-Negative Prostate Cancer

抄録

Introduction: Androgen receptor (AR)-targeted therapies are the first-line treatment for metastatic prostate cancer. However, resistance inevitably develops in most cases, resulting in castration-resistant prostate cancer (CRPC). CRPCs can be classified into 3 subtypes: AR-positive CRPC (ARPC), neuroendocrine prostate cancer (NEPC), and double-negative prostate cancer (DNPC), which lacks both AR and neuroendocrine markers. DNPC is associated with poor prognosis and limited therapeutic options, representing a significant clinical challenge. The aim of this study is to analyze the molecular characteristics of the 3 CRPC subtypes and to identify therapeutic targets for DNPC.

Methods: We characterized the molecular signature of diverse CRPC models using gene expression profiles from publicly available datasets. We then analyzed the effect of inhibiting potential therapeutic targets using LNCaP cells and DU145 cells as models for ARPC and DNPC, respectively.

Results: We classified 40 CRPC models, including human prostate cancer organoids, patient-derived xenografts, and cell lines, into ARPC, NEPC, and DNPC by Uniform Manifold Approximation and Projection (UMAP) analysis. Integrated analysis using weighted gene co-expression network analysis (WGCNA) and gene set enrichment analysis (GSEA) revealed specific signaling pathways characterizing each subtype. Although both WGCNA and GSEA suggested activation of transforming growth factor-beta (TGF-β) signaling in DNPC, inhibition of TGF-β signaling failed to suppress the migratory activity of DU145 cells. In contrast, inhibition of MEK/ERK signaling, another signaling pathway upregulated in DNPC, suppressed both the migration and proliferation of DU145 cells.

Conclusions: Inhibition of MEK/ERK signaling may represent a promising therapeutic strategy for DNPC.