Identification of resistance mechanisms to small-molecule inhibition of YAP/TEAD-regulated transcription [RNA-seq]

The Hippo tumour 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 now entering clinical trials for different cancers. Here, we investigated the cellular response to TEAD palmitoylation inhibitors, using genomic and genetic strategies. Genome-wide CRISPR/Cas9 screens revealed that mutations in genes from the Hippo, MAPK and JAK-STAT signaling pathways all modulate the cellular response to TEAD inhibition. Inhibition of TEAD palmitoylation strongly reduced YAP/TEAD target expression, whilst only mildly impacting YAP/TEAD genome binding. Additionally, expression of MAPK pathway genes was induced upon inhibition of TEAD palmitoylation, which coincided with YAP/TEAD redistribution to AP-1 transcription factor binding sites. Consistent with this, combined inhibition of TEAD and the MAPK protein MEK, synergistically blocked proliferation of several mesothelioma and lung cancer cell lines and more potently reduced the growth of patient-derived lung cancers 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.