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 18F-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.
Nature cancer. 2023 Apr 10 [Epub ahead of print]
Martin K Bakht, Yasutaka Yamada, Sheng-Yu Ku, Varadha Balaji Venkadakrishnan, Joshua A Korsen, Teja M Kalidindi, Kei Mizuno, Shin Hye Ahn, Ji-Heui Seo, Maria Mica Garcia, Francesca Khani, Olivier Elemento, Henry W Long, Alain Chaglassian, Nagavarakishore Pillarsetty, Jason S Lewis, Matthew Freedman, Anthony P Belanger, Quang-De Nguyen, Himisha Beltran
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA., Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Harvard Medical School, Boston, MA, USA., Department of Pathology and Laboratory Medicine, Weill Cornell Medical Center, New York Presbyterian Hospital, New York, NY, USA., Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA., Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA., Blue Earth Diagnostics, Burlington, MA, USA., Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. .