Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells in human renal cell carcinoma is a primary target for therapy by tyrosine kinase inhibitors

We determined whether therapy for human renal cell carcinoma (HRCC) that grows in the kidney of nude mice by the specific epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, PKI166, is directed against phosphorylated EGFR on tumor cells or on tumor-associated endothelial cells. EGFR(+)/transforming growth factor alpha (TGF-alpha)(-) SN12-PM6 HRCC cells were transfected with full-length sense TGF-alpha cDNA or vector control. SN12-PM6 cells expressing low or high levels of TGF-alpha were implanted into the kidney of nude mice. Only tumors produced by TGF-alpha(+) HRCC cells contained tumor-associated endothelial cells expressing activated EGFR. Oral administration of PKI166 produced significant therapy only in TGF-alpha(+) tumors, which correlated with apoptosis of tumor-associated endothelial cells. These data suggest that the production of TGF-alpha by HRCC cells leads to the activation of EGFR on tumor-associated endothelial cells that serve as an essential target for therapy with tyrosine kinase inhibitors.