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 language | English (US) |
|---|---|
| Pages (from-to) | 31666-31681 |
| Number of pages | 16 |
| Journal | Oncotarget |
| Volume | 8 |
| Issue number | 19 |
| DOIs | |
| State | Published - 2017 |
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Keywords
- Neurofibromatosis type 2
- PDGFR
- Schwannoma
- SRC
- STAT3
ASJC Scopus subject areas
- Oncology
Cite this
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 journal › Article
}
TY - JOUR
T1 - Ponatinib promotes a G1 cell-cycle arrest of merlin/NF2-deficient human schwann cells
AU - Petrilli, Alejandra M.
AU - Garcia, Jeanine
AU - Bott, Marga
AU - Plati, Stephani Klingeman
AU - Dinh, Christine T
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
PY - 2017
Y1 - 2017
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.
KW - Neurofibromatosis type 2
KW - PDGFR
KW - Schwannoma
KW - SRC
KW - STAT3
UR - http://www.scopus.com/inward/record.url?scp=85019068190&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85019068190&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.15912
DO - 10.18632/oncotarget.15912
M3 - Article
AN - SCOPUS:85019068190
VL - 8
SP - 31666
EP - 31681
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 19
ER -