Oncotarget

Research Papers:

Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells

Alejandra M. Petrilli, Jeanine Garcia, Marga Bott, Stephani Klingeman Plati, Christine T. Dinh, Olena R. Bracho, Denise Yan, Bing Zou, Rahul Mittal, Fred F. Telischi, Xue-Zhong Liu, Long-Sheng Chang, D. Bradley Welling, Alicja J. Copik and Cristina Fernández-Valle _

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Oncotarget. 2017; 8:31666-31681. https://doi.org/10.18632/oncotarget.15912

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Abstract

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

Correspondence to:

Cristina Fernández-Valle, email: cfv@ucf.edu

Keywords: neurofibromatosis type 2, schwannoma, PDGFR, SRC, STAT3

Received: August 17, 2016    Accepted: February 20, 2017    Published: March 06, 2017

ABSTRACT

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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