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

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., INFbeta) 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 INFgamma from CD3 and CD8 cells. These findings support VT00278 as a promising candidate for GEAC treatment, either alone or in combination with immunotherapy.