VT103

Cardiac fibroblasts (CFs) are the primary cells tasked with depositing and remodeling collagen and significantly associated with heart failure (HF). TEAD1 has been shown to be essential for heart development and homeostasis. However, fibroblast endogenous TEAD1 in cardiac remodeling remains incompletely understood. Transcriptomic analyses revealed consistently upregulated cardiac TEAD1 expression in mice 4 weeks after transverse aortic constriction (TAC) and Ang-II infusion. Further investigation revealed that CFs were the primary cell type expressing elevated TEAD1 levels in response to pressure overload. Conditional TEAD1 knockout was achieved by crossing TEAD1-floxed mice with CFs- and myofibroblasts-specific Cre mice. Echocardiographic and histological analyses demonstrated that CFs- and myofibroblasts-specific TEAD1 deficiency and treatment with TEAD1 inhibitor, VT103, ameliorated TAC-induced cardiac remodeling. Mechanistically, RNA-seq and ChIP-seq analysis identified Wnt4 as a novel TEAD1 target. TEAD1 has been shown to promote the fibroblast-to-myofibroblast transition through the Wnt signalling pathway, and genetic Wnt4 knockdown inhibited the pro-transformation phenotype in CFs with TEAD1 overexpression. Furthermore, co-immunoprecipitation combined with mass spectrometry, chromatin immunoprecipitation, and luciferase assays demonstrated interaction between TEAD1 and BET protein BRD4, leading to the binding and activation of the Wnt4 promoter. In conclusion, TEAD1 is an essential regulator of the pro-fibrotic CFs phenotype associated with pathological cardiac remodeling via the BRD4/Wnt4 signalling pathway.

The BRAF V600E mutation is observed in 2% of the patients with lung adenocarcinoma (LUAD), and combination therapy targeting BRAF and mitogen‐activated protein kinase (MEK) is the standard treatment for this population. However, acquired resistance inevitably develops, which highlights the need for novel therapeutic strategies. In this study, we established a patient‐derived BRAF V600E‐mutated LUAD cell line, KTOR81, and investigated the potential of targeting the Yes‐associated protein 1 (YAP1)/transcriptional enhanced associate domain 1 (TEAD1) pathway in combination with BRAF inhibition. We observed that the novel TEAD1 inhibitor VT103 enhanced the efficacy of the BRAF inhibitor dabrafenib in KTOR81 cells and xenograft models. The combination of dabrafenib and VT103 downregulated the expression of the antiapoptotic protein survivin, which is transcriptionally regulated by the YAP1/TEAD1 complex, leading to increased apoptosis. Moreover, we used a LUAD tissue microarray to compare the staining patterns of YAP1, TEAD1, and survivin, and examined their association with prognosis. These analyses revealed a strong correlation between YAP1, TEAD1, and survivin expression in LUAD, suggesting the relevance of the YAP1/TEAD1‐survivin axis beyond BRAF V600E‐mutated cases. While no statistically significant association was observed between survivin expression and prognosis, when limited to driver oncogene‐positive patients, high survivin expression was suggested to be associated with poor prognosis. These findings provide preclinical evidence for the efficacy of combining TEAD1 inhibition with BRAF‐targeted therapy in BRAF V600E‐mutated LUAD and highlight the YAP1/TEAD1‐survivin axis as a potential therapeutic target especially in the driver oncogene‐positive LUAD patients.