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.

5α‐reductase inhibitors; benign prostatic hyperplasia; c‐Kit; drug resistance; patient‐derived organoids.