Group I Paks as therapeutic targets in NF2-deficient meningioma
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Hoi-Yee Chow1,*, Biao Dong2,*, Sergio G. Duron3, David A. Campbell3, Christy C. Ong4, Klaus P. Hoeflich4, Long-Sheng Chang5,6,7, D. Bradley Welling7, Zeng-jie Yang1, Jonathan Chernoff1
1Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA
2Department of Microbiology and Immunology, Sol Sherry Thrombosis Research Center, Temple University, Philadelphia, Pennsylvania 19104, USA
3Afraxis Inc., La Jolla, California 92037, USA
4Department of Translational Oncology, Genentech, South San Francisco, California 94080, USA
5Center for Childhood Cancer, The Research Institute at Nationwide Children’s Hospital, The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
6Department of Pediatrics, The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
7Department of Otolaryngology, The Ohio State University College of Medicine, Columbus, Ohio 43205, USA
*These authors contributed equally to this work
Jonathan Chernoff, e-mail: Jonathan.Chernoff@fccc.edu
Keywords: protein kinases, p21-activated kinase, neurofibromatosis, meningioma, signal transduction, small molecule inhibitors
Received: October 02, 2014 Accepted: November 24, 2014 Published: January 24, 2015
Neurofibromatosis type 2 (NF2) is an autosomal dominant disorder characterized by the development of multiple tumors in the central nervous system, most notably schwannomas and meningiomas. Mutational inactivation of NF2 is found in 40–60% of sporadic meningiomas, but the molecular mechanisms underlying malignant changes of meningioma cells remain unclear. Because group I p21-activated kinases (Paks) bind to and are inhibited by the NF2-encoded protein Merlin, we assessed the signaling and anti-tumor effects of three group-I specific Pak inhibitors - Frax597, 716 and 1036 - in NF2−/− meningiomas in vitro and in an orthotopic mouse model. We found that these Pak inhibitors suppressed the proliferation and motility of both benign (Ben-Men1) and malignant (KT21-MG1) meningiomas cells. In addition, we found a strong reduction in phosphorylation of Mek and S6, and decreased cyclin D1 expression in both cell lines after treatment with Pak inhibitors. Using intracranial xenografts of luciferase-expressing KT21-MG1 cells, we found that treated mice showed significant tumor suppression for all three Pak inhibitors. Similar effects were observed in Ben-Men1 cells. Tumors dissected from treated animals exhibited an increase in apoptosis without notable change in proliferation. Collectively, these results suggest that Pak inhibitors might be useful agents in treating NF2-deficient meningiomas.
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