HOMEPRODUCTSCOMPANYCONTACTFAQResearchDictionaryPharmaSign Up FREE or Login

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

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.
AuthorsLong-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
JournalPloS one (PLoS One) Vol. 16 Issue 7 Pg. e0252048 ( 2021) ISSN: 1932-6203 [Electronic] United States
PMID34264955 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Neurofibromin 2
  • Organophosphorus Compounds
  • Pyrimidines
  • Protein-Tyrosine Kinases
  • brigatinib
Topics
  • Cell Proliferation
  • Humans
  • Meningeal Neoplasms (genetics)
  • Meningioma (genetics)
  • Mutation
  • Neurilemmoma (genetics, pathology)
  • Neurofibromin 2 (deficiency, genetics)
  • Organophosphorus Compounds (pharmacology)
  • Protein-Tyrosine Kinases (antagonists & inhibitors)
  • Pyrimidines (pharmacology)

Join CureHunter, for free Research Interface BASIC access!

Take advantage of free CureHunter research engine access to explore the best drug and treatment options for any disease. Find out why thousands of doctors, pharma researchers and patient activists around the world use CureHunter every day.
Realize the full power of the drug-disease research graph!


Choose Username:
Email:
Password:
Verify Password:
Enter Code Shown: