Journal Article

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

Bessler, Waylan K., He, Yongzheng, La Rosa, Salvatore, Erdin, Serkan, Johnson, Gary L., Thomas, Craig, Yates, Charles W., Ramesh, Vijaya, Fernandez-Valle, Cristina, Morrison, Helen, Beauchamp, Roberta L., Angus, Steven P., Yuan, Jin, Lu, Qingbo, Smith, Abbi E., Zhang, Xiaohu, Dixon, Shelley A. H., Plotkin, Scott R., Haggarty, Stephen J., Poi, Ming, Riecken, Lars Björn, Gusella, James F., Oblinger, Janet L., Chang, Long-Sheng, Huang, Jie, Stemmer-Rachamimov, Anat O., Petrilli, Alejandra M., Masters, Andrea, Blakeley, Jaishri O., Ferrer, Marc, Li, Xiaohong, Jones, David R., Guha, Rajarshi, Gilbert, Thomas S. K., Jiang, Li, Welling, D. Bradley, Clapp, D. Wade, Burns, Sarah S., Guinney, Justin, Hawley, Eric

2021

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anaplastic Lymphoma Kinase - antagonists & inhibitors / Anaplastic Lymphoma Kinase - genetics / Anaplastic Lymphoma Kinase - metabolism / Animal models / Animals / Autosomal dominant inheritance / Biology and Life Sciences / Blood diseases / Brain cancer / Cancer / Care and treatment / Cell Line, Tumor / Consortia / EphA2 protein / Focal adhesion kinase / Genetic disorders / Genetic engineering / Hospitals / Humans / Kinases / Medical schools / Medicine / Medicine and Health Sciences / Meningeal Neoplasms - drug therapy / Meningeal Neoplasms - genetics / Meningeal Neoplasms - pathology / Meningioma / Meningioma - drug therapy / Meningioma - genetics / Meningioma - pathology / Mice / Morbidity / Mutation / Neurilemmoma - drug therapy / Neurilemmoma - genetics / Neurilemmoma - pathology / Neurofibromatosis / Neurofibromatosis 2 / Neurofibromatosis 2 - drug therapy / Neurofibromatosis 2 - genetics / Neurofibromatosis 2 - pathology / Neurofibromin 2 / Neurofibromin 2 - deficiency / Neurofibromin 2 - genetics / Neurofibromin 2 - metabolism / Neurological disorders / Neurology / Organophosphorus Compounds - pharmacology / Otolaryngology / Pediatrics / Pharmacy / Protein Kinase Inhibitors - pharmacology / Protein-Tyrosine Kinases - antagonists & inhibitors / Protein-Tyrosine Kinases - genetics / Protein-Tyrosine Kinases - metabolism / Pyrimidines - pharmacology / Research and Analysis Methods / Schwann cells / Target recognition / Therapeutic targets / Tumor suppressor genes / Tumors / Tyrosine / Xenograft Model Antitumor Assays / Xenografts / Xenotransplantation