Cited by 497HER2/EGFR in Cancer ResearchLung Cancer Treatments and MutationsGastric Cancer Management and Outcomes

Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network

Ritter, Christoph A., Perez-Torres, Marianela, Rinehart, Cammie, Guix, Marta, Dugger, Teresa, Engelman, Jeffrey A., Arteaga, Carlos L.·2007·Clinical Cancer Research

Abstract

PURPOSE: We have investigated mechanisms of acquired resistance to the HER2 antibody trastuzumab in BT-474 human breast cancer cells. EXPERIMENTAL DESIGN: BT-474 xenografts established in athymic nude mice were eliminated by trastuzumab. Continuous cell lines (HR for Herceptin resistant) were generated from tumors that recurred in the presence of continuous antibody therapy. RESULTS: The isolated cells behaved resistant to trastuzumab in culture as well as when reinjected into nude mice. They retained HER2 gene amplification and trastuzumab binding and were exquisitely sensitive to peripheral blood mononuclear cells ex vivo in the presence of the antibody. The HR cells exhibited higher levels of phosphorylated epidermal growth factor receptor (EGFR) and EGFR/HER2 heterodimers. Phosphorylation of HER2 in HR cells was inhibited by the EGFR tyrosine kinase inhibitors erlotinib and gefitinib. Gefitinib also inhibited the basal association of p85 with phosphorylated HER3 in HR cells. Both inhibitors as well as the dual EGFR/HER2 inhibitor, lapatinib, induced apoptosis of the HR cells in culture. Growth of established HR5 xenografts was inhibited by erlotinib in vivo. In addition, the HR cells overexpressed EGFR, transforming growth factor alpha, heparin-binding EGF, and heregulin RNAs compared with the parental trastuzumab-sensitive cells. CONCLUSIONS: These results are consistent with the inability of trastuzumab to block the heterodimerization of HER2 and suggest that amplification of ligand-induced activation of ErbB receptors is a plausible mechanism of acquired resistance to trastuzumab that should be investigated in primary mammary cancers.

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Crossref · 10.1158/1078-0432.ccr-07-0701

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  • In laboratory models of HER2-amplified breast cancer treated with trastuzumab, increased levels of EGFR and ERBB ligands led to an increase in active EGFR/HER3 and EGFR/HER2 dimers to promote resistance.

    “In laboratory models of HER2-amplified breast cancer treated with trastuzumab, increased levels of EGFR and ERBB ligands led to an increase in active EGFR/HER3 and EGFR/HER2 dimers to promote resistance (Ritter et al., 2007).”

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Authors
Ritter, C. A., Perez-Torres, M., Rinehart, C., Guix, M., Dugger, T., Engelman, J. A., & Arteaga, C. L.
Affiliations
  • Universität Greifswald (DE)
  • 2Medicine and
  • Harvard University (US)
  • Vanderbilt University (US)
Venue
Clinical Cancer Research
Published
2007-08-15
Volume
13
Issue
16
Pages
4909-4919
ISSN
  • 1078-0432 (ISSN-L)
  • 1557-3265
OpenAlex
W2080518844
Cited by
497
References
60
Citations by year
2026: 4 · 2025: 7 · 2024: 8 · 2023: 30 · 2022: 12 · 2021: 18 · 2020: 15 · 2019: 16 · 2018: 22 · 2017: 20 · 2016: 30 · 2015: 35 · 2014: 41 · 2013: 48 · 2012: 48
FWCI
15.97
Type
journal article
Language
en
Open access
closed
Locations
  • Clinical Cancer Research (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (R01CA080195, T32CA078136, CA80195, CA 78136, P50CA098131, P30CA068485)
Topics
  • Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Gastric Cancer Management and Outcomes
Keywords
trastuzumab resistance, HER2, epidermal growth factor receptor, HER3, neuregulin-1, transforming growth factor-alpha, heparin-binding EGF, erlotinib, gefitinib, lapatinib, HER2 amplification, acquired drug resistance, xenografts
MeSH terms
Trastuzumab, Animals, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Female, Ligands, Mice, Inbred BALB C, Signal Transduction, Transforming Growth Factor alpha, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Cell Line, Tumor, Mice, Antibodies, Monoclonal, Humanized, ErbB Receptors

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