Targeting the Hippo pathway in cancers via ubiquitination dependent TEAD degradation

The Hippo pathway is among the most frequently altered key signaling pathways in cancer. TEAD1-4 are essential transcription factors and key downstream effectors in the Hippo pathway. Here we identified RNF146 as a ubiquitin ligase (E3) that can catalyze TEAD ubiquitination and negatively regulate their function in cells. We show that this ubiquitin of TEADs is governed by their PARylation state and validated the genetic interaction between RNF146 and the Hippo pathway in cancer cell lines and the model organism Drosophila melanogaster . Furthermore, we demonstrate that pharmacologically induced ubiquitination of TEADs by heterobifunctional chemical inducers of protein degradation (CIDE) molecules can promote potent pan-TEAD degradation. These TEAD-CIDEs can effectively suppress activation of TEAD target genes in a dose-dependent manner and exhibited significant anti-proliferative effects in Hippo-dependent tumor cells, thus phenocopy the effect of genetic ablation of TEAD protein. Collectively, this study demonstrates a post-translational mechanism of TEAD protein regulation and provides a proof-of-concept demonstration that pharmacological induced TEAD ubiquitination could be an effective therapeutic strategy to target Hippo-driven cancers. ### Competing Interest Statement All authors except M. C. and A.A. were employed by Genentech Inc at the time of the research.