Oncotarget

Research Papers:

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

Scott Troutman, Susana Moleirinho, Smitha Kota, Kendall Nettles, Mohammad Fallahi, Gary L. Johnson and Joseph L. Kissil _

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Oncotarget. 2016; 7:54515-54525. https://doi.org/10.18632/oncotarget.10248

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Abstract

Scott Troutman1, Susana Moleirinho1, Smitha Kota1, Kendall Nettles1, Mohammad Fallahi2, Gary L. Johnson3, Joseph L. Kissil1

1Department of Cancer Biology, The Scripps Institute, Jupiter, FL, 33458, USA

2Department of Informatics Core, The Scripps Institute, Jupiter, FL, 33458, USA

3Department of Pharmacology, University of North Carolina, Chapel Hill, NC, 27599, USA

Correspondence to:

Joseph L. Kissil, email: jkissil@scripps.edu

Keywords: neurofibromatosis, NF2, signal transduction, crizotinib, FAK

Received: January 04, 2016     Accepted: May 13, 2016     Published: June 23, 2016

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.


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