DDDR-14. TEAD inhibitor VT3989, in combination with Brigatinib prevents <i>NF2</i> -deficient meningioma and schwannoma growth

Abstract NF2-related Schwannomatosis (NF2-SWN) is a hereditary cancer predisposition syndrome, resulting in the development of schwannomas, meningiomas and ependymomas. Surgical resection is the predominant modality of treatment, with limited options for inoperable and recurrent tumours. Hippo signalling dysregulation, a hallmark of NF2 loss, is the primary therapeutic target for NF2-related drug discovery. VT3989, a small molecule inhibitor, has demonstrated anti-proliferative activity in NF2-deficient schwannoma, by blocking the palmitoylation of TEAD, essential for Hippo pathway-mediated transcription (Laraba et al, 2023). However, hyperactivation of proliferation, conferring resistance to TEAD inhibition has recently been observed (Kulkarni et al, 2024). We aimed to identify a therapeutic regimen for dual pathway inhibition; an in-silico compound screen identified the tyrosine kinase inhibitor, brigatinib, as a top candidate for use in combination with VT3989. Initial screening of brigatinib demonstrated a significant dose-dependent inhibition of proliferation and initiation of apoptosis across immortalised and primary NF2-deficient tumour cells. Subsequent, high-throughput dose optimisation of the VT3989-brigatinib combinational therapy, exhibited synergistic growth-inhibition in low grade meningioma. Preclinical in vivo studies were performed using an intracranial orthotopic meningioma xenograft model and the Postn;Cre-NF2fl/fl schwannoma model. The VT3989-brigatinib combination significantly reduced growth of NCH93-Luc meningioma xenografts compared to monotherapy and vehicle controls. Furthermore, proliferation within the Postn;Cre dorsal root and vestibular ganglia schwannomas were significantly reduced. Western blotting determined that the combination treatment modulated various kinases (AKT, ERK and FAK), and TEAD driven transcriptional activity to induce its anti-neoplastic effect. Therefore, ongoing global and phospho-proteomic analysis will identify specific proteins, phospho-sites, and signalling cascades dysregulated by the combination therapy. Further validation of these processes is underway to identify synthetic lethality targets and determine the mechanism behind VT3989 and brigatinib synergy. Together, our data demonstrates the therapeutic efficacy of VT3989 in combination with brigatinib, highlighting its potential clinical benefit for future NF2-SWN patients.