Dysregulation of the Hippo pathway is a common finding in mesothelioma, leading to constitutive YAP activation. NF2 is a negative regulator of YAP, the major effector of Hippo signaling. NF2-deficient mesothelioma, often due to biallelic inactivating NF2 mutations (NF2m), is dependent on interactions between YAP and TEAD for growth. VT3989 is an oral, highly potent and selective inhibitor of TEAD palmitoylation and blocks YAP function, a pathway previously considered undruggable. Preclinical studies demonstrated good activity in NF2 deficient models.