Hippo–YAP/TAZ
The pathway that tells organs when to stop growing. Cancers disable it so YAP and TAZ stay in the nucleus driving growth; in mesothelioma, NF2 loss does exactly that, and the first drugs against the YAP–TEAD switch are in trials.
Mechanical and contact cues activate the Hippo kinases MST1/2–LATS1/2, which phosphorylate and exclude YAP/TAZ from the nucleus. NF2 (Merlin) loss (mesothelioma, meningioma), LATS loss, and YAP/TAZ fusions (epithelioid haemangioendothelioma) unleash YAP/TAZ–TEAD transcription. TEAD palmitoylation-pocket inhibitors (IK-930, VT3989, IAG933) are in phase 1/2, notably in NF2-mutant mesothelioma and as combinations to overcome KRAS/EGFR-inhibitor resistance, where YAP is a bypass route. YAP also drives stiffness-induced signalling and CAF activation.
In one picture
A building inspector (Hippo) who checks that the block is full and stops new floors. Cancers fire the inspector, and the architect (YAP/TAZ) keeps adding storeys.
Diagram
top- TEAD inhibitors (VT3989, IK-930, IAG933) in NF2-mutant mesothelioma and with KRAS/EGFR inhibitors
- Verteporfin repurposing (preclinical)
- Combination rationale: YAP bypass after MAPK inhibition
Notes
top- Leading programmes: Camargo (Stanford), Guan (UCSD), Pan (Johns Hopkins) on Hippo biology; Vivace Therapeutics, Ikena, Novartis on TEAD inhibitors.
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