Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription

The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ target genes. Consistent with this, combined inhibition of TEAD and the MAPK kinase MEK, synergistically blocks proliferation of multiple mesothelioma and lung cancer cell lines and more potently reduces the growth of patient-derived lung cancer xenografts in vivo. Collectively, we reveal mechanisms by which cells can overcome small-molecule inhibition of TEAD palmitoylation and potential strategies to enhance the anti-tumor activity of emerging Hippo pathway targeted therapies. Synopsis Genome-wide CRISPR/Cas9 screens identify mechanisms by which mesothelioma cells respond to TEAD palmitoylation inhibitors, which are the first Hippo pathway targeted therapies. MAPK pathway targeted therapies enhance the anti-tumor activity of TEAD inhibitors. Mutating the Hippo, MAPK, and JAK-STAT pathways modulates the cellular response to TEAD inhibitors. MAPK pathway hyperactivation confers resistance to TEAD inhibition by reinstating expression of a subset of YAP/TAZ targets. Combined inhibition of TEAD and MEK synergistically blocks proliferation of mesothelioma and lung cancer cell lines. MEK inhibitors enhance the ability of TEAD inhibitors to suppress the growth of patient-derived lung cancer xenografts. Genome-wide CRISPR/Cas9 screens identify mechanisms by which mesothelioma cells respond to TEAD palmitoylation inhibitors, which are the first Hippo pathway targeted therapies. MAPK pathway targeted therapies enhance the anti-tumor activity of TEAD inhibitors.