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This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.

Abstract

Neurofibromatosis Type 2 (NF2) is an autosomal dominant genetic syndrome caused by mutations in the NF2 tumor suppressor gene resulting in multiple schwannomas and meningiomas. There are no FDA approved therapies for these tumors and their relentless progression results in high rates of morbidity and mortality. Through a combination of high throughput screens, preclinical in vivo modeling, and evaluation of the kinome en masse, we identified actionable drug targets and efficacious experimental therapeutics for the treatment of NF2 related schwannomas and meningiomas. These efforts identified brigatinib (ALUNBRIG®), an FDA-approved inhibitor of multiple tyrosine kinases including ALK, to be a potent inhibitor of tumor growth in established NF2 deficient xenograft meningiomas and a genetically engineered murine model of spontaneous NF2 schwannomas. Surprisingly, neither meningioma nor schwannoma cells express ALK. Instead, we demonstrate that brigatinib inhibited multiple tyrosine kinases, including EphA2, Fer and focal adhesion kinase 1 (FAK1). These data demonstrate the power of the de novo unbiased approach for drug discovery and represents a major step forward in the advancement of therapeutics for the treatment of NF2 related malignancies.

Details

Title
Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK
Author
Long-Sheng, Chang; Oblinger, Janet L; Smith, Abbi E; Ferrer, Marc; Angus, Steven P; Hawley, Eric; Petrilli, Alejandra M; Beauchamp, Roberta L; Lars Björn Riecken; Erdin, Serkan; Poi, Ming; Huang, Jie; Bessler, Waylan K; Zhang, Xiaohu; Guha, Rajarshi; Craig, Thomas; Burns, Sarah S; Gilbert, Thomas S K; Jiang, Li; Li, Xiaohong; Lu, Qingbo; Yuan, Jin; He, Yongzheng; Dixon, Shelley A H; Masters, Andrea; Jones, David R; Yates, Charles W; Haggarty, Stephen J; Salvatore La Rosa; D Bradley Welling; Stemmer-Rachamimov, Anat O; Plotkin, Scott R; Gusella, James F; Guinney, Justin; Morrison, Helen; Ramesh, Vijaya; Fernandez-Valle, Cristina; Johnson, Gary L; Blakeley, Jaishri O; D Wade Clapp; on behalf of the Synodos for NF2 Consortium
First page
e0252048
Section
Research Article
Publication year
2021
Publication date
Jul 2021
Publisher
Public Library of Science
e-ISSN
19326203
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2552047445
Copyright
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication: https://creativecommons.org/publicdomain/zero/1.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.