Landscape of prostate-specific membrane antigen heterogeneity and regulation in AR-positive and AR-negative metastatic prostate cancer.

Bakht Martin K and Yamada Yasutaka and Ku Sheng-Yu and Venkadakrishnan Varadha Balaji and Korsen Joshua A and Kalidindi Teja M and Mizuno Kei and Ahn Shin Hye and Seo Ji-Heui and Garcia Maria Mica and Khani Francesca and Elemento Olivier and L

Tumor expression of prostate-specific membrane antigen (PSMA) is lost in 15-20\% of men with castration-resistant prostate cancer (CRPC), yet the underlying mechanisms remain poorly defined. In androgen receptor (AR)-positive CRPC, we observed lower PSMA expression in liver lesions versus other sites, suggesting a role of the microenvironment in modulating PSMA. PSMA suppression was associated with promoter histone 3 lysine 27 methylation and higher levels of neutral amino acid transporters, correlating with F-fluciclovine uptake on positron emission tomography imaging. While PSMA is regulated by AR, we identified a subset of AR-negative CRPC with high PSMA. HOXB13 and AR co-occupancy at the PSMA enhancer and knockout models point to HOXB13 as an upstream regulator of PSMA in AR-positive and AR-negative prostate cancer. These data demonstrate how PSMA expression is differentially regulated across metastatic lesions and in the context of the AR, which may inform selection for PSMA-targeted therapies and development of complementary biomarkers.

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April, 2023



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