Abstract 6918: TEAD inhibition as a therapeutic strategy for diffuse-type gastric cancer

Abstract Introduction: Diffuse-type gastric cancer (DGC) accounts for one third of gastric cancers and is associated with poor differentiation, discohesive growth, chemoresistance, and worse survival compared to intestinal-type tumors. DGC is typically genomically stable, and there are no approved DGC-targeted therapies. Recent studies utilizing multi-omic profiling of patient samples and DGC mouse models have identified a tumor-promoting role for Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif (YAP/TAZ), which interact with TEAD transcription factors to regulate gene expression. Therefore, we evaluated the activity and mechanism of TEAD inhibitors in DGC preclinical models. Methods: Gastric cancer patient-derived organoids (PDOs) and cell lines were treated with TEAD inhibitors (VT103, VT107) and/or 5-fluorouracil (5-FU) for in vitro assays evaluating cell proliferation or invasion. The in vivo activity of VT103 and/or 5-FU was tested with a subcutaneous xenograft model using a genetically engineered mouse model of gastric cancer driven by oncogenic KrasG12D and loss of Trp53/Cdh1. Results: TEAD inhibition with VT103 and VT107 reduced proliferation, colony formation, and invasion in DGC cell lines and PDOs. We observed no effect of TEAD inhibitors on the viability of a normal gastric tissue cell line. Combining the TEAD1-selective inhibitor VT103 with 5-FU chemotherapy resulted in further reduction of DGC PDO viability relative to monotherapy. In flank tumors, inhibition of the YAP/TAZ-TEAD pathway using VT-103 in combination with 5-FU significantly reduced tumor growth. We hypothesized that TEAD inhibition blocks an epithelial-to-mesenchymal transition (EMT) program and promotes apoptosis. Consistent with this hypothesis, TEAD1 inhibition with VT-103 reduced expression of the EMT marker Slug and increased expression of the apoptosis marker cleaved caspase 3 in tumor xenografts. Conclusions: The YAP/TAZ-TEAD pathway is an important driver of gastric cancer growth and metastasis, particularly in DGC where it may promote EMT. TEAD inhibition reduces gastric cancer growth and invasion in vitro and in vivo in preclinical models and demonstrates synergistic activity with 5-FU chemotherapy. These results suggest a potential role for further investigation of clinical efficacy of TEAD inhibitors in patients with DGC. Citation Format: Lawrence W. Wu, Sung Joo Jang, Jimyung Park, Cameron Shapiro, Tracy T. Tang, Ryan H. Moy. TEAD inhibition as a therapeutic strategy for diffuse-type gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6918.