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Oncotarget. 2016 Aug 23;7(34):54515-54525. doi: 10.18632/oncotarget.10248.

Crizotinib inhibits NF2-associated schwannoma through inhibition of focal adhesion kinase 1.

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Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
Department of Informatics Core, The Scripps Institute, Jupiter, FL, 33458, USA.
Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA.


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.


FAK; NF2; crizotinib; neurofibromatosis; signal transduction

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