Multiple genetic aberrations in human
gliomas contribute to their highly infiltrative and rapid growth characteristics.
Focal adhesion kinase (FAK) regulates
tumor migration and invasion.
Insulin-like growth factor-I receptor (IGF-IR), whose expression correlates with
tumor grade, is involved in proliferation and survival. We hypothesized that inhibiting the phosphorylation of FAK and IGF-IR by NVP-TAE226 (hereafter called
TAE226), a novel dual
tyrosine kinase inhibitor of FAK and IGF-IR, would suppress the growth and invasion of
glioma cells. In culture,
TAE226 inhibited extracellular matrix-induced autophosphorylation of FAK (Tyr(397)).
TAE226 also inhibited
IGF-I-induced phosphorylation of IGF-IR and activity of its downstream target genes such as MAPK and Akt.
TAE226 retarded
tumor cell growth as assessed by a cell viability assay and attenuated G(2)-M cell cycle progression associated with a decrease in
cyclin B1 and phosphorylated cdc2 (Tyr(15))
protein expression.
TAE226 treatment inhibited
tumor cell invasion by at least 50% compared with the control in an in vitro
Matrigel invasion assay. Interestingly,
TAE226 treatment of
tumor cells containing wild-type p53 mainly exhibited G(2)-M arrest, whereas
tumor cells bearing mutant p53 underwent apoptosis. Induction of apoptosis by
TAE226 was substantiated by detection of
caspase-3/7 activation and
poly(ADP-ribose) polymerase cleavage and by an
Annexin V apoptosis assay. More importantly,
TAE226 treatment significantly increased the survival rate of animals in an intracranial
glioma xenograft model. Collectively, these data show that blocking the signaling pathways of FAK and IGF-IR with
TAE226 has the potential to be an efficacious treatment for human
gliomas.