Targeting EGFR activity in tumor-derived endothelial cells.

5704 The target cells for anti-cancer Epidermal Growth Factor Receptor (EGFR) inhibitors, Iressa, Tarceva, and Erbitux are typically thought to be tumor cells. We provide evidence that tumor-derived endothelial cells (TECs) can also be direct-targets of anti-EGFR therapeutics. TECs isolated from xenografts of melanoma, liposarcoma, and breast carcinoma express EGFR at higher levels than normal endothelial cells (NECs). EGFR expressed on the TECs is activated by members of the EGF family of ligands (EGF, HB-EGF, TGFΑ). EGFR on the TECs acts in a heterodimer with the oncogene ErbB2 and activation of these receptors is coupled to MAPK activation. TECs display increased proliferation in a dose dependent manner to EGF, whereas the NECs are non-responsive to EGF. EGFR kinase inhibitor, AG1478, inhibits both EGF induced cell proliferation as well as exponential growth of TECs in complete media. Melanoma cells themselves were negative for EGFR expression and non-responsive to EGF. Melanoma derived ECs (Mel-ECs) are selective targets of anti-EGFR drugs since their normal counterparts the Skin-ECs are not as sensitive to the EGFR kinase inhibitor. In vivo expression of EGFR and activated-EGFR in ECs of EGFR negative melanoma xenografts was observed by immunohistochemical analyses. Our data suggests that anti-EGFR therapeutics may be effective in patients tested negative for EGFR immunoreactivity on their tumor cells, through the targeting of these drugs to the tumor vasculature.