ZD6474 is a novel, orally available inhibitor of
vascular endothelial growth factor (
VEGF) receptor-2 (
KDR) tyrosine kinase, with additional activity against
epidermal growth factor receptor (EGFR)
tyrosine kinase.
ZD6474 has been shown to inhibit angiogenesis and
tumor growth in a range of
tumor models.
Gefitinib ("
Iressa") is an selective EGFR
tyrosine kinase inhibitor (TKI) that blocks signal transduction pathways. We examined the antitumor activity of
ZD6474 in the
gefitinib-sensitive
lung adenocarcinoma cell line, PC-9, and a
gefitinib-resistant variant (PC-9/ZD). PC-9/ZD cells showed cross-resistance to
ZD6474 in an in vitro
dye formation assay. In addition,
ZD6474 showed dose-dependent inhibition of EGFR phosphorylation in PC-9 cells, but inhibition was only partial in PC-9/ZD cells. ZD6474-mediated inhibition of
tyrosine residue phosphorylation (Tyr992 and Tyr1045) on EGFR was greater in PC-9 cells than in PC-9/ZD cells. These findings suggest that the inhibition of EGFR phosphorylation by
ZD6474 can contribute a significant, direct growth-inhibitory effect in tumor cell lines dependent on EGFR signaling for growth and/or survival. The effect of
ZD6474 (12.5-50 mg/kg/day p.o. for 21 days) on the growth of PC-9 and PC-9/ZD
tumor xenografts in athymic mice was also investigated. The greatest effect was seen in
gefitinib-sensitive PC-9
tumors, where
ZD6474 treatment (>12.5 mg/kg/day) resulted in
tumor regression. Dose-dependent growth inhibition, but not
tumor regression, was seen in ZD6474-treated PC-9/ZD
tumors. These studies demonstrate that the additional EGFR TKI activity may contribute significantly to the antitumor efficacy of
ZD6474, in particular in those
tumors that are dependent on continued EGFR-signaling for proliferation or survival. In addition, these results provide a preclinical rationale for further investigation of
ZD6474 as a potential treatment option for both EGFR-TKI-sensitive and EGFR-TKI-resistant
tumors.