Co-targeting EZH2 and TEAD elicits apoptosis through tumor-intrinsic innate immune signaling in Hippo pathway-mutated cancers - RNA-seq data from genetic disruption of EZH2

TEA/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 RNA-seq derived from pharmacologic disruption of EZH2. Overall design: MSTO-211H malignant pleural mesothelioma cells were transiently transfected with Cas9 and either an sgRNA control guide (sgCTRL) or a guide targeting EZH2 (EZH2-KO). RNA-seq profiling of sgCTRL and EZH2-KO cells treated with DMSO or a TEAD inhibitor, MYF-03-69 for 24h, was then performed.