Inhibition of YAP/TAZ-driven TEAD activity prevents growth of NF2-null schwannoma and meningioma

Laraba et al. report new roles for Hippo signalling in NF2-null meningioma and schwannoma. Their work uses a novel TEAD inhibitor to block growth of these two tumour types in vitro and in vivo, paving the way for their clinical use, and identifies TAZ-dependent expression of the cancer stem cell marker ALDH1A1 in tumours. Schwannoma tumours typically arise on the eighth cranial nerve and are mostly caused by loss of the tumour suppressor Merlin (NF2). There are no approved chemotherapies for these tumours and the surgical removal of the tumour carries a high risk of damage to the eighth or other close cranial nerve tissue. New treatments for schwannoma and other NF2-null tumours such as meningioma are urgently required. Using a combination of human primary tumour cells and mouse models of schwannoma, we have examined the role of the Hippo signalling pathway in driving tumour cell growth. Using both genetic ablation of the Hippo effectors YAP and TAZ as well as novel TEAD palmitoylation inhibitors, we show that Hippo signalling may be successfully targeted in vitro and in vivo to both block and, remarkably, regress schwannoma tumour growth. In particular, successful use of TEAD palmitoylation inhibitors in a preclinical mouse model of schwannoma points to their potential future clinical use. We also identify the cancer stem cell marker aldehyde dehydrogenase 1A1 (ALDH1A1) as a Hippo signalling target, driven by the TAZ protein in human and mouse NF2-null schwannoma cells, as well as in NF2-null meningioma cells, and examine the potential future role of this new target in halting schwannoma and meningioma tumour growth.

Automated summary

The study reports new roles for the Hippo signalling pathway in NF2-null meningioma and schwannoma, and identifies the cancer stem cell marker ALDH1A1 as a target of Hippo signalling. The novel TEAD inhibitor used in the study effectively blocks the growth of these tumour types, providing potential clinical applications.