Open AccessBrigatinib causes tumor shrinkage in both NF2-deficient meningioma and schwannoma through inhibition of multiple tyrosine kinases but not ALK
Author(s) -
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 Bessler,
Xiaohu Zhang,
Rajarshi Guha,
Craig J. Thomas,
Sarah Burns,
Samuel F. Gilbert,
Li Jiang,
Xiaohong Li,
Qingbo Lu,
Yi Jin,
Yongzheng He,
Shelley Dixon,
Andrea R. Masters,
David R. Jones,
Charles W. Yates,
Stephen J. Haggarty,
Salvatore La Rosa,
D. Bradley Welling,
Anat StemmerRachamimov,
Scott R. Plotkin,
James F. Gusella,
Justin Guinney,
Helen Morrison,
Vijaya Ramesh,
Cristina FernándezValle,
Gary L. Johnson,
Jaishri O. Blakeley,
D. Wade Clapp
Publication year - 2021
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0252048
Subject(s) - neurofibromatosis type 2 , merlin (protein) , cancer research , kinome , meningioma , medicine , tyrosine kinase inhibitor , tyrosine kinase , receptor tyrosine kinase , alectinib , schwannoma , kinase , anaplastic lymphoma kinase , pathology , cancer , biology , suppressor , receptor , lung cancer , microbiology and biotechnology , malignant pleural effusion
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.