Effects of trastuzumab on epidermal growth factor receptor‐dependent and ‐independent human colon cancer cells

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Abstract
Little information is available as to the potential role of HER‐2 as a therapeutic target in colon cancers, which express much fewer HER‐2 receptors than breast cancer cells. Treatment of certain human colon cancer cell lines with the HER‐2 inhibitory antibody mAb 4D5 demonstrated a role for HER‐2 in mediating proliferation, apoptosis and tumorigenicity. However, only the cell lines that were dependent on autocrine EGFR‐mediated cell proliferation were susceptible to the antiproliferative and antitumorigenic effects of HER‐2 inhibition. The relative levels of HER‐2, EGFR, HER‐3 and HER‐4 were not predictive of responsiveness to mAb 4D5. Treatment with HER‐2 antibodies caused a decrease in HER‐2 protein levels in all of the colon cancer cell lines and also significantly decreased EGFR levels but only in the EGFR‐dependent cell lines. Treatment with mAb 4D5 caused the rapid ubiquitination and ligand‐dependent downregulation of the EGFR in an EGFR‐dependent colon cancer cell line. Treatment of athymic mice engrafted with EGFR‐dependent colon cancer cells with mAb 4D5 caused tumor regression and a decrease in EGFR tyrosine phosphorylation in the tumor cells. EGFR‐independent colon cancer cell xenografts were resistant to mAb 4D5 therapy. Combined inhibition of HER‐2 and EGFR caused large areas of necrosis in EGFR‐dependent colon cancer xenografts, suggesting a benefit of combined HER‐2 and EGFR inhibitor therapy. Predicting clinical responsiveness of human colon cancer cells to anti‐HER‐2 and anti‐EGFR therapy may require demonstration of EGFR tyrosine kinase dependency of the cells.

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