title: Effects of trastuzumab on epidermal growth factor receptor-dependent and -independent human colon cancer cells.
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.
authors.affiliation: Department of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah 84112, USA. scott.kuwada@hsc.utah.edu
authors.forename: Scott K
authors.initials: SK
authors.lastname: Kuwada
authors.forename: Courtney L
authors.initials: CL
authors.lastname: Scaife
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Kuang
authors.forename: Xiufen
authors.initials: X
authors.lastname: Li
authors.forename: Robert F
authors.initials: RF
authors.lastname: Wong
authors.forename: Scott R
authors.initials: SR
authors.lastname: Florell
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Coffey
authors.forename: Phillip D
authors.initials: PD
authors.lastname: Gray
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002455:Cell Division; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D004815:Epidermal Growth Factor / Q000378:metabolism; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D000068878:Trastuzumab; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D025801:Ubiquitin