Imaging and targeting S1PR1 in HER2+ tumors.

Human Epidermal Growth Factor Receptor 2 (HER2) is a membrane receptor tyrosine kinase overexpressed in a subset of gastric cancers and is the target of multiple clinically approved therapies, including the antibody-drug conjugate trastuzumab deruxtecan (T-DXd). However, resistance to HER2-directed therapies remains a major challenge in gastric cancer. Sphingosine-1-phosphate receptor 1 (S1PR1), a G-protein-coupled receptor involved in oncogenic signaling, has been associated with poor prognosis and therapy resistance. This study investigated the role of S1PR1 in modulating response to HER2-targeted therapy and explored therapeutic dual targeting of HER2 and S1PR1. We used immunohistochemistry, Western blot analyses, and S1PR1-targeted radiotracer to assess S1PR1 expression in patient-derived xenograft samples and preclinical tumor models. We observed decreased S1PR1 in tumors that responded to T-DXd and trastuzumab therapy. In contrast, tumors with persistent S1PR1 expression exhibited resistance to HER2-targeted therapy. The S1PR1 inhibitor fingolimod, when combined with T-DXd, significantly enhanced therapeutic efficacy in HER2+/S1PR1+ tumors, resulting in reduced HER2 and S1PR1 protein levels and decreased tumor volume. This work demonstrates that S1PR1 expression is associated with resistance to HER2-targeted therapy, and S1PR1 PET has potential as a biomarker for selecting patients for HER2-targeted therapy, and S1PR1 has the potential to monitor T-DXd therapeutic response.