GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE302nnn/GSE302321/primaryOK200GenomicsHomo sapiensGenome binding/occupancy profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE302321GEOGSEfalseCo-targeting EZH2 and TEAD elicits apoptosis through tumor-intrinsic innate immune signaling in Hippo pathway-mutated cancers - ChIP-seq data from genetic disruption of EZH2TEA/TEF-domain [TEAD] inhibitors are being evaluated in clinical trials for cancers with alterations in the Hippo pathway including mesothelioma. We recently developed and showcased the potency of TEAD palmitoylation inhibitors MYF-03-69 and MYF-03-176 in mesothelioma cell lines. However, TEAD inhibition results in cell cycle arrest in cell line models with Hippo pathway alterations without inducing cell death, potentially limiting their long-term clinical efficacy. Using a genome-wide CRISPR/Cas9 screen, we identified EZH2 as a critical modulator of the cellular response to TEAD inhibition. Compared to single agent treatments, EZH2i/TEADi robustly triggered apoptosis and suppressed the growth of Hippo-mutated cells in vitro and in vivo. Mechanistically, EZH2i/TEADi-treated cells exhibited heightened activation of tumor-intrinsic innate immune signaling which resulted in DNA damage and subsequent apoptosis. Taken together, we propose this novel combinatorial strategy as a potential approach to enhancing the anti-tumor efficacy of single agent TEAD targeting therapies in Hippo pathway altered tumors. This GEO accession includes the data series associated with ChIP-seq derived from genetic disruption of EZH2.2026/07/17GSE302321GSM9101839GSM9101836GSM9101858GSM9101857GSM9101835GSM9101838GSM9101859GSM9101837GSM9101843GSM9101865GSM9101864GSM9101842GSM9101867GSM9101845GSM9101866GSM9101844GSM9101861GSM9101860GSM9101863GSM9101841GSM9101840GSM9101862GSM9101829GSM9101828GSM9101847GSM9101846GSM9101868GSM9101849GSM9101848GSM9101832GSM9101854GSM9101831GSM9101853GSM9101856GSM9101834GSM9101833GSM9101855GSM9101850GSM9101852GSM9101830GSM910185124676302321Homo sapiens