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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.

Author information

1
Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA.
2
Department of Informatics Core, The Scripps Institute, Jupiter, FL, 33458, USA.
3
Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA.

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.

KEYWORDS:

FAK; NF2; crizotinib; neurofibromatosis; signal transduction

PMID:
27363027
PMCID:
PMC5342359
DOI:
10.18632/oncotarget.10248
[Indexed for MEDLINE]
Free PMC Article

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