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

Kuwada SK, Scaife CL, Kuang J, Li X, Wong RF, Florell SR, Coffey RJ, Gray PD
Int J Cancer. 2004 109 (2): 291-301

PMID: 14750183 · DOI:10.1002/ijc.11686

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.

Copyright 2003 Wiley-Liss, Inc.

MeSH Terms (18)

Animals Antibodies, Monoclonal Antibodies, Monoclonal, Humanized Antineoplastic Agents Apoptosis Cell Division Colonic Neoplasms Epidermal Growth Factor ErbB Receptors Female Humans Mice Mice, Nude Phosphorylation Protein-Tyrosine Kinases Receptor, ErbB-2 Trastuzumab Ubiquitin

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