title: Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1.
abstract: Neurofibromatosis type 2 (NF2) is a dominantly inherited autosomal disease characterized by schwannomas of the 8th cranial nerve. The NF2 tumor suppressor gene encodes for Merlin, a protein implicated as a suppressor of multiple cellular signaling pathways. To identify potential drug targets in NF2-associated malignancies we assessed the consequences of inhibiting the tyrosine kinase receptor MET. We identified crizotinib, a MET and ALK inhibitor, as a potent inhibitor of NF2-null Schwann cell proliferation in vitro and tumor growth in vivo. To identify the target/s of crizotnib we employed activity-based protein profiling (ABPP), leading to identification of FAK1 (PTK2) as the relevant target of crizotinib inhibition in NF2-null schwannoma cells. Subsequent studies confirm that inhibition of FAK1 is sufficient to suppress tumorigenesis in animal models of NF2 and that crizotinib-resistant forms of FAK1 can rescue the effects of treatment. These studies identify a FDA approved drug as a potential treatment for NF2 and delineate the mechanism of action in NF2-null Schwann cells.
authors.affiliation: Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Troutman
authors.affiliation: Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
authors.forename: Susana
authors.initials: S
authors.lastname: Moleirinho
authors.affiliation: Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
authors.forename: Smitha
authors.initials: S
authors.lastname: Kota
authors.affiliation: Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
authors.forename: Kendall
authors.initials: K
authors.lastname: Nettles
authors.affiliation: Department of Informatics Core, The Scripps Institute, Jupiter, FL, 33458, USA.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Fallahi
authors.affiliation: Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Johnson
authors.affiliation: Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Kissil
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D000077547:Crizotinib; D051417:Focal Adhesion Kinase 1 / Q000037:antagonists & inhibitors*; D006801:Humans; D051379:Mice; D009442:Neurilemmoma / Q000188:drug therapy*; D025581:Neurofibromin 2 / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D025581:Neurofibromin 2; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011725:Pyridines; D000077547:Crizotinib; D051417:Focal Adhesion Kinase 1
keywords: FAK; NF2; crizotinib; neurofibromatosis; signal transduction