Genetic and pharmacological disruption of the TEAD–YAP complex suppresses the oncogenic activity of YAP

TLDR

In Drosophila, the TEAD ortholog Scalloped is essential for Yki‑driven overgrowth yet dispensable for normal tissue growth, implying that the mammalian TEAD–YAP axis could be targeted to selectively inhibit YAP‑driven oncogenesis. The study tests this hypothesis through genetic and pharmacologic interventions. A dominant‑negative TEAD selectively blocks YAP‑mediated hepatomegaly and tumorigenesis without affecting normal liver growth, and the small molecule verteporfin disrupts TEAD–YAP binding and YAP‑induced liver overgrowth, demonstrating that TEAD–YAP inhibition is a viable therapeutic strategy against YAP oncogenic activity.

Abstract

The Drosophila TEAD ortholog Scalloped is required for Yki-mediated overgrowth but is largely dispensable for normal tissue growth, suggesting that its mammalian counterpart may be exploited for selective inhibition of oncogenic growth driven by YAP hyperactivation. Here we test this hypothesis genetically and pharmacologically. We show that a dominant-negative TEAD molecule does not perturb normal liver growth but potently suppresses hepatomegaly/tumorigenesis resulting from YAP overexpression or Neurofibromin 2 (NF2)/Merlin inactivation. We further identify verteporfin as a small molecule that inhibits TEAD–YAP association and YAP-induced liver overgrowth. These findings provide proof of principle that inhibiting TEAD–YAP interactions is a pharmacologically viable strategy against the YAP oncoprotein.