Abstract 4535: Targeting YAP1 and DKK1 pathways to suppress peritoneal carcinomatosis in gastric adenocarcinoma

Abstract Peritoneal carcinomatosis (PC), characterized by malignant ascites cells or implants, affects approximately 45% of advanced gastric adenocarcinoma (GAC) patients and is associated with a poor prognosis, with survival rates often less than six months. Despite its prevalence and severe impact, the molecular mechanisms underlying PC in GAC remain poorly understood, highlighting a significant unmet need for targeted therapies. Our previous studies demonstrated that YAP is highly expressed in PC cells, promoting cancer stem cell (CSC)-like properties and correlating with decreased patient survival. Here, we observed that high YAP1 expression is inversely correlated with CD8+ T cell infiltration in GAC. RNA sequencing analysis revealed a significant reduction in DKK1 expression upon YAP1 depletion, and both YAP and DKK1 were highly expressed in PC cells. High expression of these markers is significantly associated with poor survival outcomes in GAC patients. Further experiments showed that ectopic DKK1 expression in YAP1 knockout cells restored cell proliferation, tumor sphere formation, cell invasion, and impaired CD8+ T cell function. Dual inhibition of YAP and DKK1 markedly reduced tumor growth and enhanced CD8+ T cell responses within the TME. Combination therapy with YAP antisense oligonucleotides (ASO), DKN1 antibody, and anti-PD-1 further extended overall survival and bolstered immune response. Our findings reveal a critical role of YAP1 in maintaining an immunosuppressive microenvironment through DKK1 in GAC with PC. This combined inhibition approach holds promise and warrants further investigation as a therapeutic strategy for GAC patients with PC. Citation Format: Yibo Fan, Shumei Song, Gengyi Zou, Longfei Huo, Ailing Scott, Ruiping Wang, Enyu Dai, Shan Shao, Linghua Wang, Shilpa Dhar, Jaffer Ajani. Targeting YAP1 and DKK1 pathways to suppress peritoneal carcinomatosis in gastric adenocarcinoma [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 4535.