{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,28]],"date-time":"2026-03-28T09:02:37Z","timestamp":1774688557415,"version":"3.50.1"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T00:00:00Z","timestamp":1676851200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 NS113854"],"award-info":[{"award-number":["R01 NS113854"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Children\u2019s Tumor Foundation Drug Discovery Initiative award"},{"name":"Department of Defense Investigator Initiated Research Award","award":["W81XWH-20-1-0222"],"award-info":[{"award-number":["W81XWH-20-1-0222"]}]},{"name":"Clinical Research Award","award":["W81XWH2210439"],"award-info":[{"award-number":["W81XWH2210439"]}]},{"name":"American Cancer Society Mission Boost","award":["MBGI-21-185-01-MBG"],"award-info":[{"award-number":["MBGI-21-185-01-MBG"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,9,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Leveraging data from our previous high-throughput drug screening in NF2 preclinical models, we identified a class of compounds targeting the ubiquitin\u2013proteasome 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\u2212\/\u2212 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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 PDGFR\u03b1, 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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/neuonc\/noad037","type":"journal-article","created":{"date-parts":[[2023,2,20]],"date-time":"2023-02-20T13:28:41Z","timestamp":1676899721000},"page":"1617-1630","source":"Crossref","is-referenced-by-count":9,"title":["Proteasomal pathway inhibition as a potential therapy for NF2-associated meningioma and schwannoma"],"prefix":"10.1093","volume":"25","author":[{"given":"Srirupa","family":"Bhattacharyya","sequence":"first","affiliation":[{"name":"Department of 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