Targeting YAP/TEAD signaling disturbs RNA Pol 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 demonstrate that VT00278, a novel compound derived from YAP/TEAD inhibitor CA3, strongly downregulated YAP/TEAD transcriptional activity and potently suppressed tumor-promoting phenotypes including proliferation, invasion and tumor sphere formation. VT00278 induced apoptosis and inhibited tumor growth in vivo especially in radiation-resistant FLO-1 XTR esophageal cancer cells. Mechanistically, in addition to impairing YAP/TEAD signal, VT00278 or YAP depletion repressed RNA polymerase II (RNAPII) transcriptional regulators, reduced RNAPII S2 phosphorylation and decreased anti-apoptotic MCL-1 expression. More interestingly, VT00278 strongly inhibited DNA damage repair, activated cytosolic DNA sensing pathway, and upregulated innate immune genes (e.g., IFNβ). Meanwhile, the upregulation of PD-L1 in VT00278-treated tumor cells possibly contributes to a suppressive immune microenvironment. In a KP-luc2 syngeneic gastric cancer 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 IFNγ from CD3 and CD8 cells. These findings support that targeting YAP/TEAD with VT00278 as a promising novel therapeutic strategy for GEAC treatment, either alone or in combination with immunotherapy.