Abstract 2663: Targeting YAP/TEAD signaling disturbs RNA polymerase II activity and enhances immunotherapy response via activated cytosolic DNA sensing pathway in gastroesophageal cancer

Abstract Gastroesophageal adenocarcinoma (GEAC) is a significant global cancer burden. Our previous studies demonstrated that YAP/TEAD are highly expressed in GEAC, and play a critical role in tumor progression, therapy resistance and metastasis. Thus, targeting YAP/TEAD signaling presents a promising therapeutic strategy. Here, we tested a novel YAP/TEAD inhibitor VT00278, a chemical analog of CA3, and showed that VT00278 strongly downregulated YAP/TEAD transcriptional activity, and potently suppressed tumor-promoting phenotypes including proliferation, invasion, tumor sphere formation; induced apoptosis and inhibited tumor growth in vivo especially in radiation resistant FLO-1 XTR GEAC cells. Mechanistically, in addition to impairing YAP/TEAD signaling, VT00278 or YAP depletion repressed RNA polymerase II (RNAPII) transcriptional regulators, reduced RNAPII S2 phosphorylation and decreased anti-apoptosis MCL-1 expression. More interestingly, VT00278 strongly induced DNA damage, activated cytosolic DNA sensing pathway, upregulated innate immune genes (e.g., INFβ) and PD-L1 expression. In a syngeneic mouse model, combining VT00278 with anti-PD-1 therapy strongly inhibited tumor growth, increased CD3+ and CD8+ T cell infiltration, and induced the production of INFγ from CD3 and CD8 cells. These findings support VT00278 as a promising candidate for GEAC treatment, either alone or in combination with immunotherapy. Citation Format: Yanting Yann Zhang, Ayna Mammedova, Dipti Athavale, Curt Balch, Mikel Ghelfi, Xiaodan Yao, Gennaro Calendo, Songjie Liu, David Pulipati, Yahui Li, Xiaoxin Chen, Francis Spitz, Generosa Grana, Vladimir Khazak, Shumei Song. Targeting YAP/TEAD signaling disturbs RNA polymerase II activity and enhances immunotherapy response via activated cytosolic DNA sensing pathway in gastroesophageal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 2663.