Imaging and targeting S1PR1 in HER2+ tumors

Sep 23, 2026

Human Epidermal Growth Factor Receptor 2 (HER2) is overexpressed in a subset of gastric cancers and targeted by approved therapies, yet resistance remains a major barrier. Sphingosine-1-phosphate receptor 1 (S1PR1) is linked to poor prognosis and therapy resistance. This study evaluated S1PR1’s role in modulating response to HER2-targeted treatment using immunohistochemistry, Western blot, and an S1PR1-targeted radiotracer across patient-derived xenografts and preclinical models.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages17

Reading Time43 min

AccessFree to download

Abstract

Introduction

Methods and Experimental Approach

Results: S1PR1 and Response to HER2 Therapy

Therapeutic Dual Targeting (HER2 and S1PR1)

Conclusions and Potential Biomarker Role

Author Manuscript Author Manuscript Author Manuscript Author Manuscript | | HHS Public Access
Author manuscript
Nucl Med Biol. Author manuscript; available in PMC 2026 January 02. | | --- | --- | Published in final edited form as: Nucl Med Biol. 2025 ; 148-149: 109057. doi:10.1016/j.nucmedbio.2025.109057 . Imaging and targeting S1PR1 in HER2+ tumors Shayla Shmuela,b, Lin Qiua, Alex Vanovera, Hong Chena, Hao Jianga, Zhude Tua, Patrícia M. R. Pereiraa,c,* a Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA bCancer Biology Graduate Program, Washington University School of Medicine, St. Louis, MO 63110, USA cAlvin J. Siteman Cancer Center, Washington University School of Medicine and Barnes-Jewish Hospital, St. Louis, MO 63110, USA Abstract 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 This is an open access article under the CC BY-NC license ([http://creativecommons.org/licenses/by-nc/4.0/](http://creativecommons.org/licenses/by-nc/4.0/)). *Corresponding author at: Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, [USA. ribeiropereirap@wustl.edu](USA. ribeiropereirap@wustl.edu) (P.M.R. Pereira). CRediT authorship contribution statement Shayla Shmuel: Writing – review & editing, Writing – original draft, Visualization, Validation, Methodology, Investigation, Formal analysis. Lin Qiu: Writing – review & editing, Methodology. Alex Vanover: Writing – review & editing, Methodology. Hong Chen: Writing – review & editing, Methodology. Hao Jiang: Writing – review & editing, Methodology. Zhude Tu: Writing – review & editing, Writing – original draft, Visualization, Supervision, Funding acquisition, Conceptualization. Patrícia M.R. Pereira: Writing – review & editing, Writing – original draft, Visualization, Supervision, Resources, Project administration, Methodology, Investigation, Funding acquisition, Formal analysis, Conceptualization. Ethics approval This study was performed according to the principles and approval of the Research Animal Resource Center and Institutional Care and Use Committee at Washington University School of Medicine in St. Louis. Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: PMRP serves as a consultant for Merck. Appendix A. Supplementary data Supplementary data to this article can be found online at [https://doi.org/10.1016/j.nucmedbio.2025.109057](https://doi.org/10.1016/j.nucmedbio.2025.109057) . Author Manuscript Author Manuscript Author Manuscript Author Manuscript

FAQs

How does S1PR1 relate to response to HER2-targeted therapies in HER2+ tumors?

Tumors that responded to trastuzumab deruxtecan (T-DXd) and trastuzumab showed decreased S1PR1, while persistent S1PR1 expression correlated with resistance to HER2-targeted therapy.

Which experimental approaches were used to assess S1PR1 in this study?

The study used immunohistochemistry, Western blot analyses, and an S1PR1-targeted radiotracer to evaluate S1PR1 expression in patient-derived xenografts and preclinical tumor models.

What effect did combining an S1PR1 inhibitor with T-DXd have in HER2+/S1PR1+ tumors?

Combining fingolimod with T-DXd significantly enhanced therapeutic efficacy, reducing HER2 and S1PR1 protein levels and decreasing tumor volume.

Sep 23, 2026

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