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Receptor-Tyrosine Kinase Inhibitor Ponatinib Inhibits Meningioma Growth In Vitro and In Vivo

Authors :
Tao Yu
Junguo Cao
Montadar Alaa Eddine
Mahmoud Moustafa
Andreas Mock
Cihan Erkut
Amir Abdollahi
Rolf Warta
Andreas Unterberg
Christel Herold-Mende
Gerhard Jungwirth
Source :
Cancers, Vol 13, Iss 23, p 5898 (2021)
Publication Year :
2021
Publisher :
MDPI AG, 2021.

Abstract

To date, there is no standard-of-care systemic therapy for the treatment of aggressive meningiomas. Receptor tyrosine kinases (RTK) are frequently expressed in aggressive meningiomas and are associated with poor survival. Ponatinib is a FDA- and EMA-approved RTK inhibitor and its efficacy in meningioma has not been studied so far. Therefore, we investigated ponatinib as a potential drug candidate against meningioma. Cell viability and cell proliferation of ponatinib-treated meningioma cells were assessed using crystal violet assay, manual counting and BrdU assay. Treated meningioma cell lines were subjected to flow cytometry to evaluate the effects on cell cycle and apoptosis. Meningioma-bearing mice were treated with ponatinib to examine antitumor effects in vivo. qPCR was performed to assess the mRNA levels of tyrosine kinase receptors after ponatinib treatment. Full-length cDNA sequencing was carried out to assess differential gene expression. IC50 values of ponatinib were between 171.2 and 341.9 nM in three meningioma cell lines. Ponatinib induced G0/G1 cell cycle arrest and subsequently led to an accumulation of cells in the subG1-phase. A significant induction of apoptosis was observed in vitro. In vivo, ponatinib inhibited meningioma growth by 72.6%. Mechanistically, this was associated with downregulation of PDGFRA/B and FLT3 mRNA levels, and mitochondrial dysfunction. Taken together, ponatinib is a promising candidate for targeted therapy in the treatment of aggressive meningioma.

Details

Language :
English
ISSN :
20726694
Volume :
13
Issue :
23
Database :
Directory of Open Access Journals
Journal :
Cancers
Publication Type :
Academic Journal
Accession number :
edsdoj.460fffe2a164da591bb1dd1d81ccfe6
Document Type :
article
Full Text :
https://doi.org/10.3390/cancers13235898