Novel TEAD1 Inhibitor VT103 Enhances Dabrafenib Efficacy in BRAF V600E Mutated Lung Adenocarcinoma via Survivin Downregulation
The BRAF V600E mutation is present in approximately 2% of patients with lung adenocarcinoma (LUAD), and the current standard of care for this subset involves combination therapy targeting both BRAF and mitogen-activated protein kinase (MEK). However, the emergence of acquired resistance remains a major clinical challenge, underscoring the need for novel therapeutic approaches.
In this study, we established KTOR81, a patient-derived LUAD cell line harboring the BRAF V600E mutation, to evaluate the therapeutic potential of targeting the Yes-associated protein 1 (YAP1)/transcriptional enhanced associate domain 1 (TEAD1) signaling pathway in combination with BRAF inhibition. Our results demonstrate that the novel TEAD1 inhibitor VT103 significantly enhances the antitumor efficacy of the BRAF inhibitor dabrafenib in both in vitro KTOR81 models and in vivo xenografts. The combination treatment led to the downregulation of survivin, an antiapoptotic protein transcriptionally regulated by the YAP1/TEAD1 complex, resulting in increased apoptotic activity.
To further explore the clinical relevance of this pathway, we analyzed a LUAD tissue microarray for the expression patterns of YAP1, TEAD1, and survivin, and assessed their correlation with patient prognosis. Our analysis revealed a strong positive correlation among YAP1, TEAD1, and survivin expression, suggesting that the YAP1/TEAD1-survivin axis may play a broader role in LUAD beyond BRAF V600E-mutated cases. Although survivin expression alone was not significantly associated with prognosis across the entire cohort, subgroup analysis indicated that in patients harboring oncogenic driver mutations, high survivin expression may be linked to poorer outcomes.
Collectively, these findings provide preclinical evidence supporting the therapeutic benefit of combining TEAD1 inhibition with BRAF-targeted therapy in BRAF V600E-mutated LUAD. Furthermore, they identify the YAP1/TEAD1-survivin axis as a promising target, particularly in LUAD patients with driver oncogene alterations.