Comprehensive Multi-Omics Analysis Identifies Molecular Subtypes and AMH-Dependent Mechanisms Driving DTX Resistance in Prostate Cancer

Abstract: Prostate cancer (PCa) remains one of the most prevalent malignancies and a leading cause of cancer-related mortality among men worldwide. Despite advancements in treatment, therapeutic resistance, particularly to docetaxel (DTX), significantly limits clinical efficacy and worsens patient outcomes. This study leveraged comprehensive transcriptomic and clinical datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to explore the molecular mechanisms underlying DTX resistance and its associated immune landscape in PCa. Differential gene expression analysis identified key resistance-related genes, enabling the stratification of patients into two distinct molecular subtypes (C1 and C2). The C1 subtype exhibited a more aggressive clinical phenotype, characterized by poorer progression-free survival, distinct mutation profiles, and significant alterations in immune-related pathways, including the enrichment of immunosuppressive components. Drug sensitivity analysis predicted differential responses to several therapeutic agents across the molecular subtypes. Single-cell transcriptomic analysis further revealed epithelial cell heterogeneity. AMH expression was associated with epithelial subpopulations characterized by reduced proliferation, lower genomic instability, and diminished DTX resistance potential, whereas AMH-low cells exhibited enhanced proliferative activity, higher mutation burden, and stronger intercellular signaling, particularly via the VEGF signaling pathway. Collectively, these findings highlight the cellular and molecular heterogeneity associated with DTX resistance in PCa and provide new insights into the molecular characteristics of DTX resistance. These results may facilitate the identification of candidate biomarkers and potential therapeutic targets, although further experimental and clinical validation is required.