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

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.

• Authors: 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
• Journal: Oncotarget (Oncotarget) Vol. 8 Issue 19 Pg. 31666-31681 (May 09 2017) ISSN: 1949-2553 [Electronic] United States
• PMID: 28427224 (Publication Type: Journal Article)

Chemical References

• Antineoplastic Agents
• Imidazoles
• Neurofibromin 2
• Paxillin
• Protein Kinase Inhibitors
• Pyridazines
• STAT3 Transcription Factor
• Cyclin D1
• Cyclin-Dependent Kinase Inhibitor p27
• ponatinib
• Receptors, Platelet-Derived Growth Factor
• Focal Adhesion Protein-Tyrosine Kinases
• src-Family Kinases
• Proto-Oncogene Proteins c-akt

Topics

• Antineoplastic Agents (pharmacology)
• Cell Line, Tumor
• Cell Survival (drug effects, genetics)
• Cyclin D1 (metabolism)
• Cyclin-Dependent Kinase Inhibitor p27 (metabolism)
• Focal Adhesion Protein-Tyrosine Kinases (metabolism)
• G1 Phase Cell Cycle Checkpoints (drug effects, genetics)
• Humans
• Imidazoles (pharmacology)
• MAP Kinase Signaling System (drug effects)
• Neurilemmoma (genetics, metabolism, pathology)
• Neurofibromin 2 (deficiency)
• Paxillin (metabolism)
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridazines (pharmacology)
• Receptors, Platelet-Derived Growth Factor (metabolism)
• STAT3 Transcription Factor (metabolism)
• Schwann Cells (drug effects, metabolism)
• Signal Transduction (drug effects)
• src-Family Kinases (metabolism)