Differential effects of low- and high-dose GW2974, a dual epidermal growth factor receptor and HER2 kinase inhibitor, on glioblastoma multiforme invasion.

Aberrant expression of epidermal growth factor receptor (EGFR; ErbB1) and HER2 (ErbB2) tyrosine kinases frequently occurs in glioblastoma multiforme (GBM) patients and is considered to be associated with tumor malignancy and poor patient prognosis. In the present study, a dual EGFR and HER2 inhibitor (GW2974) was evaluated for its effects in GBM in vitro and in vivo. Results showed that low-concentration GW2974 inhibited GBM cell invasion, whereas a high concentration of the same compound counteracted this effect. Similar results were observed in an intracranial GBM xenograft model, in which, although both doses of GW2974 slowed tumor growth, no improvement in survival was observed in mice treated with high-dose GW2974, presumably because of the augmentation of tumor invasion. By protein microarray and Western blot analyses, the p38 mitogen-activated protein kinase (MAPK) pathway was found to be activated in GBM cells under high-concentration GW2974. Additionally, blockage of the p38 MAPK pathway reproduced the inhibitory effect of low-concentration GW2974 on cell invasion. These data suggest that the p38 MAPK pathway might contribute to the differential regulation of cell invasion by GW2974. Taken together, our results indicate that GW2974 exerts different effects in GBM depending on drug dosage. This offers a new perspective on the role of GW2974 in tumor progression, providing a potential strategy for GBM treatment based on precise prescription.