Hippo 肿瘤抑制通路通过调节 YAP 和 TAZ 的核丰度来控制转录，从而通过 TEAD1-TEAD4 DNA 结合蛋白激活转录。最近，报道了几种 YAP 和 TEAD 的小分子抑制剂，其中一些进入了针对 Hippo 通路失调的不同癌症（最引人注目的是间皮瘤）的临床试验。使用全基因组 CRISPR/Cas9 筛选，我们发现 Hippo、MAPK 和 JAK-STAT 信号通路的基因突变均可调节间皮瘤细胞系对 TEAD 棕榈酰化抑制剂的反应。通过探索突变细胞的基因表达程序，我们发现 MAPK 通路过度激活通过恢复 YAP/TAZ 靶基因子集的表达来赋予对 TEAD 抑制的抵抗力。与此一致的是，联合抑制 TEAD 和 MAPK 激酶 MEK，可以协同阻断多种间皮瘤和肺癌细胞系的增殖，并更有效地减少体内患者来源的肺癌异种移植物的生长。总的来说，我们揭示了细胞克服 TEAD 棕榈酰化小分子抑制的机制，以及增强新兴 Hippo 通路靶向治疗的抗肿瘤活性的潜在策略。© 2024。作者。

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.© 2024. The Author(s).