Imaging and targeting S1PR1 in HER2+ tumors

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.