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Anticancer effects of ZD6474, a VEGF receptor tyrosine kinase inhibitor, in gefitinib (“Iressa”)‐sensitive and resistant xenograft models

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 anti‐tumor 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.