Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma

Background: Neurofibromatosis type 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. Tumors associated with NF2, including schwannomas and meningiomas, are resistant to chemotherapy and often recur despite surgery and/or radiation. These tumors typically show only cytostatic responses to signal transduction inhibitors, underscoring the need for more effective cytotoxic therapies.

Methods: Building on data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP). We then investigated the efficacy of three UPP inhibitors—ixazomib (MLN9708), pevonedistat (MLN4924), and TAK-243 (MLN7243). Using human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and Nf2-/- mouse SCs, we conducted dose-response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA sequencing to explore the underlying mechanisms of apoptosis. In vivo efficacy was evaluated in orthotopic NF2-deficient meningioma and schwannoma tumor models.

Results: Among the three UPP inhibitors tested, ixazomib and TAK-243 significantly reduced cell viability and induced apoptosis, while pevonedistat showed no such effect. In vitro analysis revealed that ixazomib and TAK-243 decreased the expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2, while upregulating genes associated with endoplasmic reticulum stress and activation of the unfolded protein response (UPR). In vivo, treatment with either ixazomib or TAK-243 led to delayed tumor growth, suggesting therapeutic potential.

Conclusions: This study demonstrates the efficacy of proteasome pathway inhibitors in preclinical models of meningioma and schwannoma and supports their potential as a novel therapeutic strategy for NF2 patients.