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.