Therapeutic approaches targeting proteins on the surface of cancer cells have emerged as an important strategy for precision oncology. To capitalize on the potential impact of drugs targeting surface proteins, detailed knowledge about the expression patterns of the target proteins in tumor tissues is required. In castration-resistant prostate cancer (CRPC), agents targeting prostate-specific membrane antigen (PSMA) have demonstrated clinical activity. However, PSMA expression is lost in a significant number of CRPC tumors. The identification of additional cell surface targets is necessary to develop new therapeutic approaches. Here, we performed a comprehensive analysis of the expression heterogeneity and co-expression patterns of trophoblast cell-surface antigen 2 (TROP2), delta-like ligand 3 (DLL3), and carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5) in CRPC samples from a rapid autopsy cohort. We show that DLL3 and CEACAM5 exhibit the highest expression in neuroendocrine prostate cancer (NEPC), while TROP2 is expressed across different CRPC molecular subtypes, except for NEPC. We further demonstrated that AR alterations were associated with higher expression of PSMA and TROP2. Conversely, PSMA and TROP2 expression was lower in RB1-altered tumors. In addition to genomic alterations, we show a tight correlation between epigenetic states, particularly histone H3 lysine 27 methylation (H3K27me3) at the transcriptional start site and gene body of TACSTD2 (encoding TROP2), DLL3, and CEACAM5, and their respective protein expression in CRPC patient-derived xenografts. Collectively, these findings provide insights into patterns and determinants of expression of TROP2, DLL3, and CEACAM5 with implications for the clinical development of cell surface targeting agents in CRPC.
NPJ precision oncology. 2024 May 17*** epublish ***
Azra Ajkunic, Erolcan Sayar, Martine P Roudier, Radhika A Patel, Ilsa M Coleman, Navonil De Sarkar, Brian Hanratty, Mohamed Adil, Jimmy Zhao, Samir Zaidi, Lawrence D True, Jamie M Sperger, Heather H Cheng, Evan Y Yu, Robert B Montgomery, Jessica E Hawley, Gavin Ha, Thomas Persse, Patricia Galipeau, John K Lee, Stephanie A Harmon, Eva Corey, Joshua M Lang, Charles L Sawyers, Colm Morrissey, Michael T Schweizer, Roman Gulati, Peter S Nelson, Michael C Haffner
Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA., Department of Urology, University of Washington, Seattle, WA, USA., Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA., Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA, USA., University of Wisconsin-Madison, Madison, WI, USA., Division of Clinical Research, Fred Hutchinson Cancer Center, Seattle, WA, USA., Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, USA., Artificial Intelligence Resource, Molecular Imaging Branch, NCI, NIH, Bethesda, MD, USA., Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA. .