1. Brigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK
- Author
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Salvatore La Rosa, Helen Morrison, Jie Huang, Rajarshi Guha, Li Jiang, Yongzheng He, Gary L. Johnson, Steven P. Angus, Eric T. Hawley, Vijaya Ramesh, Justin Guinney, Sarah S. Burns, Jin Yuan, Roberta L. Beauchamp, Lars Björn Riecken, Cristina Fernandez-Valle, Marc Ferrer, Charles W. Yates, Serkan Erdin, Abbi Smith, Waylan K. Bessler, D. Bradley Welling, D. Wade Clapp, Shelley Dixon, Scott R. Plotkin, Ming Poi, Thomas S. K. Gilbert, Anat Stemmer-Rachamimov, Alejandra M. Petrilli, Craig J. Thomas, Xiaohong Li, Qingbo Lu, David R. Jones, James F. Gusella, Long-Sheng Chang, Andrea R. Masters, Xiaohu Zhang, Janet L. Oblinger, Jaishri O. Blakeley, and Stephen J. Haggarty
- Subjects
0301 basic medicine ,Macroglial Cells ,Cancer Treatment ,Schwannoma ,Biochemistry ,Tyrosine Kinases ,0302 clinical medicine ,Medical Conditions ,Animal Cells ,Medicine and Health Sciences ,Meningeal Neoplasms ,Kinome ,Neurofibromatosis type 2 ,Neurological Tumors ,Neurofibromin 2 ,Multidisciplinary ,Pharmaceutics ,Animal Models ,Protein-Tyrosine Kinases ,EPH receptor A2 ,Enzymes ,Oncology ,Neurology ,Experimental Organism Systems ,Genetic Diseases ,030220 oncology & carcinogenesis ,Medicine ,Cellular Types ,Meningioma ,Tyrosine kinase ,Neurilemmoma ,Research Article ,Brigatinib ,Tumor suppressor gene ,Science ,Mouse Models ,Glial Cells ,Research and Analysis Methods ,03 medical and health sciences ,Model Organisms ,Organophosphorus Compounds ,Drug Therapy ,medicine ,otorhinolaryngologic diseases ,Humans ,neoplasms ,Cell Proliferation ,Clinical Genetics ,business.industry ,Autosomal Dominant Diseases ,Cancers and Neoplasms ,Biology and Life Sciences ,Proteins ,Cell Biology ,medicine.disease ,nervous system diseases ,030104 developmental biology ,Pyrimidines ,Neurofibromatosis Type 2 ,Mutation ,Cancer research ,Animal Studies ,Enzymology ,Schwann Cells ,business ,Protein Kinases - 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.
- Published
- 2021