Work

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

Year: 2016

Type: article

Abstract: // Scott Troutman 1 , Susana Moleirinho 1 , Smitha Kota 1 , Kendall Nettles 1 , Mohammad Fallahi 2 , Gary L. Johnson 3 , Joseph L. Kissil 1 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 Correspondence to: Joseph L. Kissil, email: [email protected] 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.

Source: Oncotarget

DOI: 10.18632/oncotarget.10248