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 Z Liu, Long Sheng Chang, D. Bradley Welling, Alicja J. Copik, Cristina Fernández-Valle

Research output: Contribution to journalArticle

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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

Fingerprint

Neurofibromatosis 2
G1 Phase Cell Cycle Checkpoints
Neurofibromin 2
Schwann Cells
Platelet-Derived Growth Factor Receptors
Acoustic Neuroma
Phosphorylation
Nervous System Neoplasms
Paxillin
70-kDa Ribosomal Protein S6 Kinases
Focal Adhesion Protein-Tyrosine Kinases
Protein Array Analysis
Cyclin D1
Neurilemmoma
Peripheral Nervous System
Tumor Suppressor Genes
ponatinib
oleoyl-estrone
Cell Survival
Flow Cytometry

Keywords

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

ASJC Scopus subject areas

  • Oncology

Cite this

Petrilli, A. M., Garcia, J., Bott, M., Plati, S. K., Dinh, C. T., Bracho, O. R., ... 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

Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells. / Petrilli, Alejandra M.; Garcia, Jeanine; Bott, Marga; Plati, Stephani Klingeman; Dinh, Christine T; Bracho, Olena R.; Yan, Denise; Zou, Bing; Mittal, Rahul; Telischi, Fred F; Liu, Xue Z; Chang, Long Sheng; Welling, D. Bradley; Copik, Alicja J.; Fernández-Valle, Cristina.

In: Oncotarget, Vol. 8, No. 19, 2017, p. 31666-31681.

Research output: Contribution to journalArticle

Petrilli, AM, Garcia, J, Bott, M, Plati, SK, Dinh, CT, Bracho, OR, Yan, D, Zou, B, Mittal, R, Telischi, FF, Liu, XZ, Chang, LS, Welling, DB, Copik, AJ & Fernández-Valle, C 2017, 'Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells', Oncotarget, vol. 8, no. 19, pp. 31666-31681. https://doi.org/10.18632/oncotarget.15912
Petrilli, Alejandra M. ; Garcia, Jeanine ; Bott, Marga ; Plati, Stephani Klingeman ; Dinh, Christine T ; Bracho, Olena R. ; Yan, Denise ; Zou, Bing ; Mittal, Rahul ; Telischi, Fred F ; Liu, Xue Z ; Chang, Long Sheng ; Welling, D. Bradley ; Copik, Alicja J. ; Fernández-Valle, Cristina. / Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells. In: Oncotarget. 2017 ; Vol. 8, No. 19. pp. 31666-31681.
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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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AU - Bracho, Olena R.

AU - Yan, Denise

AU - Zou, Bing

AU - Mittal, Rahul

AU - Telischi, Fred F

AU - Liu, Xue Z

AU - Chang, Long Sheng

AU - Welling, D. Bradley

AU - Copik, Alicja J.

AU - Fernández-Valle, Cristina

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N2 - 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.

AB - 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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