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

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

doi:10.18632/oncotarget.15912

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.

Highlights

Neurofibromatosis type 2 (NF2) is a non-malignant tumor disorder affecting the peripheral and central nervous systems
We found that depletion of merlin expression was associated with increased levels of p-PDGFRα/β and p-SRC compared to the parental human Schwann cells (HSC) (Figure 1B)
This finding agrees with previous reports of increased activation of the platelet-derived growth factor receptor (PDGFR) and SRC pathways in human schwannomas compared to normal human nerve [10, 20, 21]

Summary

Introduction

Neurofibromatosis type 2 (NF2) is a non-malignant tumor disorder affecting the peripheral and central nervous systems. NF2 is caused by mutations in the NF2 gene that encodes the tumor suppressor protein known as merlin or schwannomin [2, 3]. Merlin modulates the activity of multiple signaling pathways that control cell size, morphology, cell adhesion, proliferation, and survival. These include receptor tyrosine kinase (RTK; e.g. ErbB2/3, PDGFR, EGFR, HGFR), small GTPases, FAK/SRC, the mammalian target of rapamycin (mTOR)/PI3K/AKT, and Hippo pathways [4]. Patients are treated off-label with the antiangiogenic agent bevacizumab that reduces edema in schwannomas without affecting the tumor cells. To date there are no FDA-approved therapies that target schwannoma cells directly and reduce morbidity and mortality of NF2 patients [1, 6]

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