The effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, against human U87 malignant glioblastoma cells

Abstract

Glioblastoma is one of the most common malignant tumors in the nervous system in both adult and pediatric patients. Studies suggest that abnormal activation of receptor tyrosine kinases contributes to pathological development of glioblastoma. However, current therapies targeting tyrosine kinase receptors have poor therapeutic outcomes. Here, we examined anticancer effects of ponatinib, a multi-targeted tyrosine kinase inhibitor, on glioblastoma cells both in the U87MG cell line and in the mouse xenograft model. We showed that ponatinib treatment reduced cell viability and induced cell apoptosis in a dose-dependent manner in U87MG cells. In addition, ponatinib suppressed migration and invasion of U87MG cells effectively. Furthermore, ponatinib-treated tumors showed an obvious reduction of tumor volume and an increase of apoptosis as compared with vehicle-treated tumors in the mouse xenograft model. These findings support a potential application of ponatinib as a chemotherapeutic option against glioblastoma cells.

Gene Fusion in Malignant Glioma: An Emerging Target for Next-Generation Personalized Treatment

“…Drugs targeting FGFR-TACC fusion genes have shown promising therapeutic potential in several types of cancer models, while clinical trials are still ongoing. To date, preclinical studies have shown a reduction of tumor growth and an increase of apoptosis upon treatment with the pan-FGFR inhibitor ponatinib in the U87MG cell line and the mouse xenograft model, suggesting a potential application of ponatinib as a chemotherapeutic option against GBM cells [60] . A phase II clinical trial studying ponatinib on recurrent GBM is now ongoing ( NCT02478164 ); however, it is not specifically designed for FGFR fusion–positive patients.…”

Beyond standard therapy: drugs under investigation for the treatment of gastrointestinal stromal tumor

“…It was shown to significantly inhibit tumor growth in in vitro and in vivo models of glioblastoma multiforme [73] and acute myeloid leukemia [74]. To elucidate the in vitro and in vivo efficacy of ponatinib, Garner and colleagues assessed the drug across a panel of GIST cell lines derived from patients with varying mutational statuses [75].…”

Identification and targeting of an FGFR fusion in a pediatric thalamic “central oligodendroglioma”

“… 41 While ponatinib has not been tested in oligodendrogliomas, it has been shown to have in vitro activity against glioblastoma cells and has caused tumor reduction and apoptosis in a murine xenograft glioblasoma model. 23 Importantly, in a murine model, ponatinib demonstrated excellent CNS penetration with a brain to plasma concentration ratio of 0.88. 22 The ability of ponatinib to cross the BBB and achieve levels that are above in vitro IC 50 levels ultimately influenced the decision to pursue treatment with ponatinib rather than pazopanib.…”

“…Due to the promising preclinical data suggesting effective in vitro and in vivo activity against glioblastoma cells and the promising characteristics of ponatinib to penetrate the central nervous system (CNS), as well a case report describing ponatinib use in a pediatric patient, we ultimately decided to initiate ponatinib for this patient. 20 – 23 The patient weighed 75 kg and was initially started on a treatment regimen of 15 mg of ponatinib daily, with a goal dose of 45 mg orally. After 2 months, the patient’s dose was increased to 30 mg daily for the second cycle.…”