{"doi":"10.1093/neuonc/noad037","title":"Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma","abstract":"BACKGROUND: Neurofibromatosis 2 (NF2) is an inherited disorder caused by bi-allelic inactivation of the NF2 tumor suppressor gene. NF2-associated tumors, including schwannoma and meningioma, are resistant to chemotherapy, often recurring despite surgery and/or radiation, and have generally shown cytostatic response to signal transduction pathway inhibitors, highlighting the need for improved cytotoxic therapies. METHODS: Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin-proteasome pathway (UPP), and undertook studies using candidate UPP inhibitors, ixazomib/MLN9708, pevonedistat/MLN4924, and TAK-243/MLN7243. Employing human primary and immortalized meningioma (MN) cell lines, CRISPR-modified Schwann cells (SCs), and mouse Nf2-/- SCs, we performed dose response testing, flow cytometry-based Annexin V and cell cycle analyses, and RNA-sequencing to identify potential underlying mechanisms of apoptosis. In vivo efficacy was also assessed in orthotopic NF2-deficient meningioma and schwannoma tumor models. RESULTS: Testing of three UPP inhibitors demonstrated potent reduction in cell viability and induction of apoptosis for ixazomib or TAK-243, but not pevonedistat. In vitro analyses revealed that ixazomib or TAK-243 downregulates expression of c-KIT and PDGFRα, as well as the E3 ubiquitin ligase SKP2 while upregulating genes associated with endoplasmic reticulum stress-mediated activation of the unfolded protein response (UPR). In vivo treatment of mouse models revealed delayed tumor growth, suggesting a therapeutic potential. CONCLUSIONS: This study demonstrates the efficacy of proteasomal pathway inhibitors in meningioma and schwannoma preclinical models and lays the groundwork for use of these drugs as a promising novel treatment strategy for NF2 patients.","journal":"Neuro-Oncology","year":2023,"id":359056,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":10,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9638,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":687837,"name":"Janet L. Oblinger","orcid":"0000-0001-6044-5624","position":1,"is_corresponding":false},{"id":354581,"name":"Roberta L. Beauchamp","orcid":null,"position":2,"is_corresponding":false},{"id":1109711,"name":"Zhenzhen Yin","orcid":"0000-0002-6022-5661","position":3,"is_corresponding":false},{"id":352795,"name":"Serkan Erdin","orcid":"0000-0001-6587-2625","position":4,"is_corresponding":false},{"id":265605,"name":"Priya Koundinya","orcid":null,"position":5,"is_corresponding":false},{"id":930853,"name":"Anna D. Ware","orcid":"0000-0002-8889-8219","position":6,"is_corresponding":false},{"id":228425,"name":"Marc Ferrer","orcid":"0000-0003-4569-9137","position":7,"is_corresponding":false},{"id":238093,"name":"Justin T. Jordan","orcid":"0000-0001-6198-817X","position":8,"is_corresponding":false},{"id":376861,"name":"Scott R. Plotkin","orcid":"0000-0002-6109-6419","position":9,"is_corresponding":false},{"id":640705,"name":"Lei Xu","orcid":"0000-0003-0525-183X","position":10,"is_corresponding":false},{"id":687840,"name":"Long‐Sheng Chang","orcid":"0000-0002-5178-2992","position":11,"is_corresponding":false},{"id":352798,"name":"Vijaya Ramesh","orcid":"0000-0003-4966-5268","position":12,"is_corresponding":false},{"id":1054630,"name":"Srirupa Bhattacharyya","orcid":null,"position":0,"is_corresponding":true}],"reference_count":52,"raw_metadata":null,"created_at":"2026-07-19T01:13:52.889556Z","pmid":"36806881","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}