Molecular Characterization of KLK2 RNA Expression in Prostate Cancer

PURPOSE: KLK2 is an androgen-regulated gene critical in prostate cancer biology with multiple KLK2-targeted therapies in clinical development. We investigated KLK2 RNA expression patterns and associations with molecular features to provide context for emerging KLK2-targeted treatments. EXPERIMENTAL DESIGN: DNA/RNA next-generation sequencing was performed on 7,078 prostate cancer specimens. KLK2-high/low RNA expression was defined as ≥75th/<25th percentiles (transcripts per million, TPM). KLK2 expression was evaluated across histologic subtypes, disease states, and metastatic sites, with correlative analyses of genomic alterations, RNA signatures, and clinical outcomes. RESULTS: KLK2 gene expression varied significantly by histology, with highest levels in adenocarcinoma [8.79 log2(TPM + 1)] and minimal expression in histologic neuroendocrine prostate cancer [0.33 log2(TPM + 1)]. Expression was significantly higher in androgen deprivation therapy (ADT)/androgen receptor pathway inhibitor (ARPI)-sensitive versus ADT/ARPI-exposed tumors [8.97 vs. 8.38 log2(TPM + 1), q < 0.001]. Localized tumors demonstrated higher expression than lymph node [8.93 vs. 8.76 log2(TPM + 1)] or distant metastases [8.23 log2(TPM + 1)], with visceral metastases showing the lowest levels. In the overall cohort, KLK2 expression correlated positively with androgen receptor signaling (r = 0.25-0.47) and negatively with neuroendocrine signaling. High KLK2 expression was associated with significantly improved overall survival (93.9 vs. 74.4 months, hazard ratio 0.68, P < 0.001) in the total cohort, with similar patterns in patients with ADT/ARPI-sensitive and ADT/ARPI-exposed disease. CONCLUSIONS: This large-scale clinico-genomic analysis reveals distinct KLK2 expression patterns across prostate cancer histologies, tumor sites, and clinical states. These findings provide a molecular framework understanding KLK2 as a therapeutic target in prostate cancer.