BKM-120 (Buparlisib): A Phosphatidyl-Inositol-3 Kinase Inhibitor with Anti-Invasive Properties in Glioblastoma.

Maria-Carmela Speranza,Prajna Behera,E Antonio Chiocca,Sean E Lawler,Michal O Nowicki,Choi-Fong Cho

doi:10.1038/srep20189

Abstract

Glioblastoma is an aggressive, invasive tumor of the central nervous system (CNS). There is a widely acknowledged need for anti-invasive therapeutics to limit glioblastoma invasion. BKM-120 is a CNS-penetrant pan-class I phosphatidyl-inositol-3 kinase (PI3K) inhibitor in clinical trials for solid tumors, including glioblastoma. We observed that BKM-120 has potent anti-invasive effects in glioblastoma cell lines and patient-derived glioma cells in vitro. These anti-migratory effects were clearly distinguishable from cytostatic and cytotoxic effects at higher drug concentrations and longer durations of drug exposure. The effects were reversible and accompanied by changes in cell morphology and pronounced reduction in both cell/cell and cell/substrate adhesion. In vivo studies showed that a short period of treatment with BKM-120 slowed tumor spread in an intracranial xenografts. GDC-0941, a similar potent and selective PI3K inhibitor, only caused a moderate reduction in glioblastoma cell migration. The effects of BKM-120 and GDC-0941 were indistinguishable by in vitro kinase selectivity screening and phospho-protein arrays. BKM-120 reduced the numbers of focal adhesions and the velocity of microtubule treadmilling compared with GDC-0941, suggesting that mechanisms in addition to PI3K inhibition contribute to the anti-invasive effects of BKM-120. Our data suggest the CNS-penetrant PI3K inhibitor BKM-120 may have anti-invasive properties in glioblastoma.

Highlights

Infiltration of normal brain parenchyma is a defining characteristic hallmark of GBM
We found that BKM-120 caused a dose-dependent, reversible blockade of GBM invasion and migration in vitro in GBM cell lines and glioma stem-like cells (GSCs)
phosphatidyl-inositol-3 kinase (PI3K) has been previously linked to cell migration in several studies[5,13], and is a major oncogenic signaling molecule in GBM1,5

Summary

Introduction

Infiltration of normal brain parenchyma is a defining characteristic hallmark of GBM. BKM-120 (Buparlisib), a dimorpholino pyrimidine derivative, is an oral pan-class I PI3K inhibitor that penetrates the blood-brain barrier (BBB)[6]. It is in clinical trials for solid tumors including GBM, and has anti-proliferative and pro-apoptotic effects in GBM cell lines independent of PTEN or EGFR status[10]. Because of the need for clinically applicable anti-invasive approaches in GBM, and the fact that BKM-120 penetrates the BBB, we investigated its effects on GBM cell migration. BKM-120 treatment led to a reduction in focal adhesions and microtubule treadmilling, which may contribute to its anti-migratory effects These data suggest that BKM-120 is a candidate anti-invasive drug for GBM therapy

Methods

Results

Conclusion