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

Abstract

Simple SummaryThe clinical management for aggressive meningiomas remains challenging due to the lack of systemic treatment options. Receptor tyrosine kinases (RTKs) are frequently overexpressed in meningiomas and are associated with poor patient survival. In this study, we evaluated the clinically approved pan-RTK inhibitor ponatinib as a novel candidate for the treatment of aggressive meningiomas. Ponatinib decreased cell viability and proliferation of meningioma cells and subsequently induced programmed cell death. Furthermore, the drug demonstrated a considerable tumor growth inhibition without causing any adverse effects in mice. Mechanistically, this was presumably caused by blocking the PDGFR signaling pathway accompanied by induction of mitochondrial dysfunction. Altogether, the multi-RTKi ponatinib may serve as a promising candidate for targeted therapy for aggressive meningiomas.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.