c‐Kit‐Mediated PI3K/AKT and Wnt/β‐Catenin Signaling Drives Resistance to 5α‐Reductase Inhibitors in Benign Prostatic Hyperplasia

Background Resistance to 5α‐reductase inhibitors (5ARIs) represents a significant therapeutic challenge in benign prostatic hyperplasia (BPH) clinical management. While the c‐Kit‐mediated signaling has been implicated in various pathological conditions, its role in BPH and 5ARI resistance remains undefined. Methods Patient‐derived organoids (PDOs) were established from BPH specimens and characterized through immunofluorescence, immunohistochemistry, and RT‐qPCR analysis. Transcriptomic profiling was performed to identify differentially expressed genes between 5ARI‐sensitive and resistant samples. The functional significance of c‐Kit‐mediated signaling was evaluated using selective inhibitor ISCK03. Further analysis identified cellular targets of c‐Kit inhibition, and downstream signaling mechanisms were characterized through pathway analysis. Results RNA sequencing revealed differentially expressed genes between 5ARI‐sensitive and resistant BPH PDOs, with significant enrichment in KIT and related genes. Enhanced c‐Kit expression was confirmed in 5ARI‐resistant specimens through multiple methodologies. Selective c‐Kit inhibition with ISCK03 specifically suppressed 5ARI‐resistant PDOs proliferation while sparing sensitive ones. Tests utilizing single‐cell‐derived organoids identified basal epithelial cells as primary targets of c‐Kit inhibition. Mechanistic studies demonstrated that c‐Kit maintains 5ARI resistance through the PI3K/AKT and Wnt/β‐catenin signaling axis, with c‐Kit inhibition significantly downregulating this pathway. Conclusions c‐Kit‐mediated signaling is associated with 5ARI resistance in BPH, potentially through modulation of PI3K/AKT and Wnt/β‐catenin pathways. These findings highlight c‐Kit as a potential therapeutic target for overcoming 5ARI resistance.