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Published on: June 13, 2014
Imaging and targeting S1PR1 in HER2+ tumors
Shayla Shmuel1, Lin Qiu2, Alex Vanover2
1Department of Radiology, Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, MO 63110, USA; Cancer Biology Graduate Program, Washington University School of Medicine, 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 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.
Insights
Sphingosine-1-phosphate receptor 1 (S1PR1) expression indicates resistance to Human Epidermal Growth Factor Receptor 2 (HER2)-targeted therapy in gastric cancer. Dual targeting of HER2 and S1PR1 enhances treatment efficacy and may serve as a predictive biomarker.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Human Epidermal Growth Factor Receptor 2 (HER2) is a key target in gastric cancer therapy.
- Resistance to HER2-targeted treatments, like trastuzumab deruxtecan (T-DXd), is a significant clinical challenge.
- Sphingosine-1-phosphate receptor 1 (S1PR1) is implicated in cancer progression and therapy resistance.
Purpose of the Study:
- To investigate the role of S1PR1 in resistance to HER2-targeted therapy.
- To explore the potential of dual targeting of HER2 and S1PR1.
- To evaluate S1PR1 as a predictive biomarker for HER2-targeted therapy response.
Main Methods:
- Immunohistochemistry and Western blot analysis to assess S1PR1 expression in patient-derived xenografts and preclinical models.
- Utilized S1PR1-targeted radiotracer for expression assessment.
- Investigated the efficacy of combining T-DXd with the S1PR1 inhibitor fingolimod.
Main Results:
- Decreased S1PR1 expression correlated with response to T-DXd and trastuzumab.
- Persistent S1PR1 expression was associated with resistance to HER2-targeted therapy.
- Combination therapy with T-DXd and fingolimod significantly improved efficacy in HER2+/S1PR1+ tumors, reducing tumor volume and protein levels.
Conclusions:
- S1PR1 expression is a marker of resistance to HER2-targeted therapy in gastric cancer.
- S1PR1 positron emission tomography (PET) may serve as a biomarker for patient selection and monitoring T-DXd treatment response.
- Dual targeting of HER2 and S1PR1 offers a promising therapeutic strategy for resistant gastric cancers.
