Mechanisms of glioblastoma cell migration and invasion: insights from the use of tyrosine kinase inhibitors

Imatinib was the first targeted tyrosine kinase inhibitor (TKI) to be approved for clinical use, and remains first-line therapy for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia (CML). The second-generation inhibitor, nilotinib, was subsequently approved for treatment of CML patients that are resistant, or develop resistance, to imatinib. Imatinib was subsequently approved as front-line therapy for the treatment of gastrointestinal stromal tumours (GISTs), but failed clinical trials for glioblastoma multiforme (GBM). The present study shows that treatment of cultured glioma cells and glioma cells isolated from human biopsies with imatinib or nilotinib strikingly increases tyrosine phosphorylation of p130Cas, focal adhesion kinase (FAK) and paxillin (PXN), resulting in enhanced cell migration and three dimensional radial invasion. Imatinib and nilotinib-induced tyrosine phosphorylation and invasion is dependent on expression of p130Cas and FAK activity, and is not dependent on known imatinib and nilotinib targets including ABL, ARG, platelet derived growth factor receptor (PDGFR) and the collagen receptor DDR1. Interestingly, findings implicate the serine / threonine phosphatase PP2A in mediating tyrosine phosphorylation of p130Cas, FAK and PXN. Inhibition of PP2A with okadaic acid significantly increased basal levels of tyrosine phosphorylation of the three proteins. Conversely, pharmacological activation of PP2A using FTY720 strongly inhibited imatinib and nilotinib stimulated tyrosine phosphorylation. Imatinib and nilotinib also stimulate tyrosine phosphorylation and radial invasion in GIST cells, a cancer for which imatinib is already approved. These TKIs also stimulate tyrosine phosphorylation of p130Cas, FAK and PXN in hepatocellular liver carcinoma cells, and in non-transformed primary cell lines. Interestingly, Imatinib and nilotinib treatment of GBM cells results in increased serine phosphorylation of p130Cas, FAK and PXN. Findings here indicate important and unforeseen adverse effects of imatinib and nilotinib treatment on key motility-related pathways, which could be a significant contributor to the lack of clinical efficacy in GBM and to the development of resistance