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, Cristina Fernández-Valle

Research output: Contribution to journalArticle

10 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)31666-31681
Number of pages16
JournalOncotarget
Volume8
Issue number19
DOIs
StatePublished - 2017

Keywords

  • Neurofibromatosis type 2
  • PDGFR
  • SRC
  • STAT3
  • Schwannoma

ASJC Scopus subject areas

  • Oncology

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    Petrilli, A. M., Garcia, J., Bott, M., Plati, S. K., Dinh, C. T., Bracho, O. R., Yan, D., Zou, B., Mittal, R., Telischi, F. F., Liu, X. Z., Chang, L. S., Welling, D. B., Copik, A. J., & Fernández-Valle, C. (2017). Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells. Oncotarget, 8(19), 31666-31681. https://doi.org/10.18632/oncotarget.15912