Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK.

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 an...

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Autores principales: Long-Sheng Chang, Janet L Oblinger, Abbi E Smith, Marc Ferrer, Steven P Angus, Eric Hawley, Alejandra M Petrilli, Roberta L Beauchamp, Lars Björn Riecken, Serkan Erdin, Ming Poi, Jie Huang, Waylan K Bessler, Xiaohu Zhang, Rajarshi Guha, Craig Thomas, Sarah S Burns, Thomas S K Gilbert, Li Jiang, Xiaohong Li, Qingbo Lu, Jin Yuan, Yongzheng He, Shelley A H Dixon, Andrea Masters, David R Jones, Charles W Yates, Stephen J Haggarty, Salvatore La Rosa, D Bradley Welling, Anat O Stemmer-Rachamimov, Scott R Plotkin, James F Gusella, Justin Guinney, Helen Morrison, Vijaya Ramesh, Cristina Fernandez-Valle, Gary L Johnson, Jaishri O Blakeley, D Wade Clapp, Synodos for NF2 Consortium
Formato: article
Lenguaje:EN
Publicado: Public Library of Science (PLoS) 2021
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Medicine
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Science
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Acceso en línea:https://doaj.org/article/d5cdd322a442449ebaffcbfad82ea6a3
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Sumario: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.

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