Abstract
BACKGROUND: Lung cancer remains the most common primary tumor to metastasize to the brain, with limited therapeutic options. In our previously published work (Shih, Nayyar et al. Nature Genetics 2020), a subset of brain metastases (BM) harbored amplifications in YAP1, offering new opportunities for targeted therapies for BM patients. New data is emerging on the relevance of the YAP/Hippo signaling pathway in the development of CNS tumors, however, therapeutically targeting this pathway has been challenging. We hypothesize that YAP1 and the associated TEAD transcriptional factors contribute to lung cancer intracranial progression and that intervention with a CNS-penetrant YAP/TEAD-targeted therapy will block brain metastasis growth. In this study, we present a novel brain-penetrant pan-TEAD inhibitor and evaluate its efficacy using both in vitro and in vivo models of lung cancer brain metastasis. METHODS: First, we evaluated TEAD inhibitor activity by measuring cell viability using CellTiterGlo in the lung cancer cells, NCI-H226, as well as gene expression of YAP target genes using qPCR. We then created an intracranial model of lung cancer brain metastases using the same cell line, and we tested the efficacy of a 3-week regimen of this novel YAP/TEAD targeted therapy, measuring intracranial tumor growth using bioluminescence imaging at 4-time points: pre-, mid-, post- and late post-treatment. RESULTS: Our data showed a decrease in cell viability upon TEAD inhibition in a dose-dependent manner, which correlates with a decrease in YAP target gene expression upon treatment. Moreover, we showed the efficacy of the novel CNS-penetrant YAP/TEAD inhibitor in controlling intracranial tumor growth, which was still maintained 3 weeks after treatment was discontinued. CONCLUSIONS: Together, our findings provide a strong rationale to further evaluate YAP/TEAD inhibition in brain metastases from lung adenocarcinoma.