Integrative Surface Antigen Profiling of KLK2 and STEAP1 in Advanced Prostate Cancer

KLK2 and STEAP1 are two cell surface targets with relevance for prostate cancer therapy. The objective of this study was to characterize the expression landscape of KLK2 and STEAP1 in metastatic castration-resistant prostate cancer (mCRPC) and to define associated transcriptomic, genomic, and epigenomic features. We analyzed a total of 1095 patient samples from three mCRPC cohorts, including in situ studies of rapid autopsy cases and patient derived xenograft models. We found that KLK2 and STEAP1 expression is strongly enriched in AR-positive tumors and largely absent in neuroendocrine and double-negative phenotypes. Within AR+ tumors, pairwise comparisons revealed co-expression and high combined positivity rates for STEAP1, KLK2, and PSMA, suggesting that co-targeting any two of these antigens increases overall tumor coverage. Analysis of samples from a rapid autopsy cohort, which enabled assessment of intra- and inter-tumoral diversity, showed comparable degrees of expression heterogeneity for KLK2 and STEAP1. Antigen expression correlated positively with AR genomic alterations and serum PSA levels, and negatively with RB1 and PTEN loss. Transcriptomic and epigenome analyses demonstrated distinct mechanisms governing antigen expression: KLK2 showed a strict AR dependence with coordinated AR/FOXA1/HOXB13 binding and enhancer activation, whereas STEAP1 was only partially AR-dependent and additionally regulated by locus-specific DNA methylation changes. Further, KLK2 and STEAP1 expression states were associated with distinct transcriptional programs and immune microenvironmental features. Implications: These findings establish KLK2 and STEAP1 as key prostate adenocarcinoma-lineage antigens and provide critical insights to inform the rational design and clinical development of cell-surface antigen-directed therapies in prostate cancer.