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
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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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).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as 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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