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Pharmacological blockade of TEAD-YAP reveals its therapeutic limitation in cancer cells

Targeting TEAD autopalmitoylation has been proposed as a therapeutic approach for YAP-dependent cancers. Here we show that TEAD palmitoylation inhibitor MGH-CP1 and analogues block cancer cell "stemness", organ overgrowth and tumor initiation in vitro and in vivo. MGH-CP1 sensitivity correlates significantly with YAP-dependency in a large panel of cancer cell lines. However, TEAD inhibition or YAP/TAZ knockdown leads to transient inhibition of cell cycle progression without inducing cell death, undermining their potential therapeutic utilities. We further reveal that TEAD inhibition or YAP/TAZ silencing leads to VGLL3-mediated transcriptional activation of SOX4/PI3K/AKT signaling axis, which contributes to cancer cell survival and confers therapeutic resistance to TEAD inhibitors. Consistently, combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death. Our work characterizes the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in cancers, and uncovers an intrinsic molecular mechanism, which confers potential therapeutic resistance.

 

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The passage you provided discusses the potential therapeutic approach of targeting TEAD autopalmitoylation in YAP-dependent cancers. The authors demonstrate that a TEAD palmitoylation inhibitor called MGH-CP1, along with its analogues, can inhibit cancer cell "stemness," organ overgrowth, and tumor initiation both in vitro and in vivo. The sensitivity to MGH-CP1 correlates with the dependency on YAP in a wide range of cancer cell lines.

However, the study reveals a limitation of TEAD inhibition or YAP/TAZ knockdown as potential therapeutic strategies. While these interventions transiently inhibit cell cycle progression, they do not induce cell death. This limitation undermines their potential as standalone therapeutic approaches.

The researchers further investigate the molecular mechanisms underlying this limitation and find that TEAD inhibition or YAP/TAZ silencing leads to the VGLL3-mediated activation of the SOX4/PI3K/AKT signaling axis. This activation promotes cancer cell survival and confers resistance to TEAD inhibitors. In other words, the inhibition of TEAD or YAP/TAZ can activate a signaling pathway that supports cancer cell survival and makes them resistant to TEAD inhibitors.

To overcome this resistance and enhance therapeutic efficacy, the authors suggest combining TEAD inhibitors with AKT inhibitors. They find that the combination of TEAD and AKT inhibitors exhibits strong synergy in inducing cancer cell death.

Overall, this work highlights both the therapeutic opportunities and limitations of TEAD palmitoylation inhibitors in YAP-dependent cancers. It also uncovers a molecular mechanism that confers potential resistance to TEAD inhibitors, which can be overcome by combining TEAD and AKT inhibitors.

Related Products

Cat.No. Product Name Information
S9735 MGH-CP1 MGH-CP1 is a potent and selective inhibitor of transcriptional enhanced associate domain (TEAD) palmitoylation. MGH-CP1 exhibits dose-dependent and potent inhibition of TEAD2/4 auto-palmitoylation in vitro with IC50 of 710 nM and 672 nM, respectively.

Related Targets

TEAD