Urokinase Plasminogen Activator Receptor-Associated Protein (uparap) As a Potential Next Generation Molecular Target for Treatment of Gastrointestinal Stromal Tumors (GIST).

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors of the gastrointestinal tract. While imatinib and other tyrosine kinase inhibitors have improved the survival of patients with advanced GIST, these treatments are not curative. Additionally, drug resistance eventually develops in most cases. Therefore, there is an unmet need to develop new therapeutic strategies for advanced GIST. This study is the first to comprehensively analyze the molecular epidemiology of urokinase plasminogen activator receptor-associated protein (uPARAP/Endo180/CD280) expression in GIST, highlighting its potential as an attractive target for targeted therapy. We analyzed uPARAP expression in GIST samples using tissue microarrays (TMAs) constructed from clinically annotated patient samples and GIST xenograft specimens. Our results demonstrated that all clinical GIST samples were positive for uPARAP expression, with high expression found in 79% (52/66) of samples. There was no statistically significant correlation between uPARAP expression and relevant clinical parameters, including gender, sample status (primary tumor or metastatic lesion), clinical outcome, mutation status, primary tumor location, and risk class, indicating that uPARAP has no prognostic role in this setting. In xenograft GIST samples, high uPARAP expression was found in 53% (8/15) of models, with a homogeneous distribution of expression in the majority of the samples. This study emphasizes the potential of uPARAP as a druggable target and paves the way for further (pre)clinical evaluation of anti-uPARAP therapy in advanced GIST.