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

UNLABELLED: Kallikrein 2 (KLK2) and six-transmembrane epithelial antigen of the prostate 1 (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 1,095 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 androgen receptor (AR)-positive tumors and largely absent in neuroendocrine and double-negative phenotypes. Within AR+ tumors, pairwise comparisons revealed coexpression and high combined positivity rates for STEAP1, KLK2, and prostate-specific membrane antigen, suggesting that cotargeting any two of these antigens increases overall tumor coverage. Analysis of samples from a rapid autopsy cohort, which enabled assessment of intra- and intertumoral diversity, showed comparable degrees of expression heterogeneity for KLK2 and STEAP1. Antigen expression correlated positively with AR genomic alterations and serum prostate-specific antigen 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. Furthermore, 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.