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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Bibliographic Details
Published in:PloS one 2021-07, Vol.16 (7), p.e0252048
Main Authors: Chang, Long-Sheng, Oblinger, Janet L, Smith, Abbi E, Ferrer, Marc, Angus, Steven P, Hawley, Eric, Petrilli, Alejandra M, Beauchamp, Roberta L, Riecken, Lars Björn, Erdin, Serkan, Poi, Ming, Huang, Jie, Bessler, Waylan K, Zhang, Xiaohu, Guha, Rajarshi, Thomas, Craig, 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, La Rosa, Salvatore, Welling, D. Bradley, 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, Clapp, D. Wade
Format: Article
Language:English
Subjects:
Animal models
Autosomal dominant inheritance
Biology and Life Sciences
Blood diseases
Brain cancer
Cancer
Care and treatment
Consortia
EphA2 protein
Focal adhesion kinase
Genetic disorders
Genetic engineering
Hospitals
Kinases
Medical schools
Medicine
Medicine and Health Sciences
Meningioma
Morbidity
Mutation
Neurofibromatosis
Neurofibromatosis 2
Neurofibromin 2
Neurological disorders
Neurology
Otolaryngology
Pediatrics
Pharmacy
Research and Analysis Methods
Schwann cells
Target recognition
Therapeutic targets
Tumor suppressor genes
Tumors
Tyrosine
Xenografts
Xenotransplantation
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Summary: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.sup.® ), 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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0252048