Molecular Characterization of KLK2 RNA Expression in Prostate Cancer.

Abstract

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. 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. 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. 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.