Phosphorylated epidermal growth factor receptor on tumor-associated endothelial cells is a primary target for therapy with tyrosine kinase inhibitors

Toshio Kuwai, Toru Nakamura, Takamitsu Sasaki, Sun Jin Kim, Dominic Fan, Gabriel J Villares, maya zigler, Hua Wang, Menashe Bar-Eli, Robert S Kerbel and Isaiah J Fidler

Year 2008, Volume 10, Issue 5

Abstract

We determined whether phosphorylated EGFR expressed on tumor-associated endothelial cells is a primary target for therapy with EGFR tyrosine kinase inhibitors (TKIs). Human colon cancer cells SW620CE2 (parental) that do not express EGFR or HER2 but express TGF-á were transduced with a lentivirus carrying non-targeting shRNA or TGF-á shRNA. The cell lines were implanted into the cecum of nude mice. Two weeks later, treatment began with saline, PKI166, or irinotecan. Endothelial cells in parental and non-targeting shRNA tumors expressed phosphorylated EGFR. Therapy with PKI166 alone or with irinotecan produced apoptosis of these endothelial cells and necrosis of the EGFR-negative tumors. Endothelial cells in tumors that did not express TGF-á did not express EGFR, and these tumors were resistant to treatment with PKI166. The response of neoplasms to EGFR antagonists has been correlated with EGFR mutations, HER2 expression, Akt activation, and EGFR gene copy number. Our present data using colon cancer cells that do not express EGFR or HER2 suggest that the expression of TGF-á by tumor cells leading to the activation of EGFR in tumor-associated endothelial cells is a major determinants for susceptibility of neoplasms to therapy by specific EGFR-TKI.

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