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

Gastroesophageal adenocarcinoma (GEAC) accounts for a significant global cancer burden. Our previous studies demonstrated that YAP1/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 developed a novel YAP/TEAD inhibitor VT00278 based on the structure of CA3 and showed that VT00278 strongly downregulated YAP/TEAD transcriptional activity, and potently suppress tumor-promoting phenotypes, including proliferation, invasion, tumor sphere formation; induce apoptosis and inhibit tumor growth in vivo especially in radiation resistant FLO-1 XTR GEAC cells. Mechanistically, in addition to impairing YAP1/TEAD signaling, VT00278 or YAP1 depletion repressed RNA polymerase II transcriptional regulators, reduced RNAPII S2 phosphorylation and decreased anti-apoptosis MCL-1 expression. More interestingly, we revealed that VT00278 strongly induced DNA damage, activated cytosolic DNA sensing pathway, upregulation of innate immune genes (e.g.INFβ) and increased PDL-1 expression. In a syngeneic mouse model, combining VT00278 with anti-PD-1 therapy synergistically inhibited tumor growth and increased CD3+ and CD8+ T cell infiltration and induced the production of INFγ from CD3 and CD8 cells in the combination treatment. These findings support VT00278 as a promising candidate for GEAC treatment, either alone or in combination with immunotherapy.