Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells
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Alejandra M. Petrilli1, Jeanine Garcia1, Marga Bott1, Stephani Klingeman Plati1, Christine T. Dinh2, Olena R. Bracho2, Denise Yan2, Bing Zou2, Rahul Mittal2, Fred F. Telischi2, Xue-Zhong Liu2, Long-Sheng Chang3, D. Bradley Welling3,4, Alicja J. Copik1 and Cristina Fernández-Valle1
1Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Lake Nona-Orlando, FL 32827, USA
2University of Miami Miller School of Medicine, Department of Otolaryngology, Miami, FL 33136, USA
3Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children’s Hospital and Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH 43205, USA
4Current Affiliation: Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Harvard University, Boston, MA 02114, USA
Cristina Fernández-Valle, email: email@example.com
Keywords: neurofibromatosis type 2, schwannoma, PDGFR, SRC, STAT3
Received: August 17, 2016 Accepted: February 20, 2017 Published: March 06, 2017
Neurofibromatosis type 2 (NF2) is a genetic syndrome that predisposes individuals to multiple benign tumors of the central and peripheral nervous systems, including vestibular schwannomas. Currently, there are no FDA approved drug therapies for NF2. Loss of function of merlin encoded by the NF2 tumor suppressor gene leads to activation of multiple mitogenic signaling cascades, including platelet-derived growth factor receptor (PDGFR) and SRC in Schwann cells. The goal of this study was to determine whether ponatinib, an FDA-approved ABL/SRC inhibitor, reduced proliferation and/or survival of merlin-deficient human Schwann cells (HSC). Merlin-deficient HSC had higher levels of phosphorylated PDGFRα/β, and SRC than merlin-expressing HSC. A similar phosphorylation pattern was observed in phospho-protein arrays of human vestibular schwannoma samples compared to normal HSC. Ponatinib reduced merlin-deficient HSC viability in a dose-dependent manner by decreasing phosphorylation of PDGFRα/β, AKT, p70S6K, MEK1/2, ERK1/2 and STAT3. These changes were associated with decreased cyclin D1 and increased p27Kip1levels, leading to a G1 cell-cycle arrest as assessed by Western blotting and flow cytometry. Ponatinib did not modulate ABL, SRC, focal adhesion kinase (FAK), or paxillin phosphorylation levels. These results suggest that ponatinib is a potential therapeutic agent for NF2-associated schwannomas and warrants further in vivo investigation.
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