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

Autor:	Chang LS; The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, The Ohio State University College of Medicine, Columbus, Ohio, United States of America., Oblinger JL; The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, The Ohio State University College of Medicine, Columbus, Ohio, United States of America., Smith AE; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Ferrer M; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America., Angus SP; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America.; University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Hawley E; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Petrilli AM; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Lake Nona-Orlando, Florida, United States of America., Beauchamp RL; Massachusetts General Hospital and Department of Neurology, Center for Genomic Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., Riecken LB; Leibniz Institute on Aging-Fritz-Lipmann Institute (FLI), Jena, Germany., Erdin S; Massachusetts General Hospital and Department of Neurology, Center for Genomic Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., Poi M; Division of Pharmacy Practice and Science, The Ohio State University College of Pharmacy, Columbus, Ohio, United States of America., Huang J; The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, The Ohio State University College of Medicine, Columbus, Ohio, United States of America., Bessler WK; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Zhang X; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America., Guha R; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America., Thomas C; Division of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, Maryland, United States of America., Burns SS; The Research Institute at Nationwide Children's Hospital and Department of Pediatrics, Center for Childhood Cancer and Blood Diseases, The Ohio State University College of Medicine, Columbus, Ohio, United States of America., Gilbert TSK; University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Jiang L; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Li X; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Lu Q; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Yuan J; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., He Y; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Dixon SAH; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Masters A; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Jones DR; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America., Yates CW; Department of Otolaryngology and Head/Neck Surgery, Indiana University School of Medicine, Indianapolis, Indiana, United States of America., Haggarty SJ; Massachusetts General Hospital and Department of Neurology, Center for Genomic Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., La Rosa S; Children's Tumor Foundation, New York, New York, United States of America., Welling DB; Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Harvard University, Boston, Massachusetts, United States of America., Stemmer-Rachamimov AO; Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America., Plotkin SR; Massachusetts General Hospital and Department of Neurology, Center for Genomic Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., Gusella JF; Center for Genomic Medicine, Massachusetts General Hospital and Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, Massachusetts, United States of America., Guinney J; Sage Bionetworks, Seattle, Washington, United States of America., Morrison H; Leibniz Institute on Aging-Fritz-Lipmann Institute (FLI), Jena, Germany., Ramesh V; Massachusetts General Hospital and Department of Neurology, Center for Genomic Medicine, Harvard Medical School, Boston, Massachusetts, United States of America., Fernandez-Valle C; Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Lake Nona-Orlando, Florida, United States of America., Johnson GL; University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America., Blakeley JO; Departments of Neurology, Neurosurgery and Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America., Clapp DW; Department of Pediatrics, Indiana University, School of Medicine, Indianapolis, Indiana, United States of America.
Jazyk:	angličtina
Zdroj:	PloS one [PLoS One] 2021 Jul 15; Vol. 16 (7), pp. e0252048. Date of Electronic Publication: 2021 Jul 15 (Print Publication: 2021).
DOI:	10.1371/journal.pone.0252048
Abstrakt:	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. Competing Interests: No authors have competing interests.
Databáze:	MEDLINE
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