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Oncotarget. 2017 May 9;8(19):31666-31681. doi: 10.18632/oncotarget.15912.

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

Author information

1
Burnett School of Biomedical Sciences, College of Medicine, University of Central Florida, Lake Nona-Orlando, FL 32827, USA.
2
University of Miami Miller School of Medicine, Department of Otolaryngology, Miami, FL 33136, USA.
3
Center 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, USA.
4
Current Affiliation: Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, Massachusetts General Hospital and Harvard University, Boston, MA 02114, USA.

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.

KEYWORDS:

PDGFR; SRC; STAT3; neurofibromatosis type 2; schwannoma

PMID:
28427224
PMCID:
PMC5458238
DOI:
10.18632/oncotarget.15912
[Indexed for MEDLINE]
Free PMC Article

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