Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells
Abstract
The majority of breast cancer patients who achieve an initial therapeutic response to the human epidermal growth factor receptor 2 (HER-2)-targeted antibody trastuzumab will show disease progression within 1 year. We previously reported the characterization of SKBR3-derived trastuzumab-resistant pools. In the current study, we show that HER-2 interacts with insulin-like growth factor-I receptor (IGF-IR) uniquely in these resistant cells and not in the parental trastuzumab-sensitive cells. The occurrence of cross talk between IGF-IR and HER-2 exclusively in resistant cells is evidenced by the IGF-I stimulation resulting in increased phosphorylation of HER-2 in resistant cells, but not in parental cells, and by the inhibition of IGF-IR tyrosine kinase activity leading to decreased HER-2 phosphorylation only in resistant cells. In addition, inhibition of IGF-IR tyrosine kinase activity by I-OMe-AG538 increased sensitivity of resistant cells to trastuzumab. HER-2/IGF-IR interaction was disrupted on exposure of resistant cells to the anti-IGF-IR antibody alpha-IR3 and, to a lesser extent, when exposed to the anti-HER-2 antibody pertuzumab. Heterodimer disruption by alpha-IR3 dramatically restored sensitivity to trastuzumab and resistant cells showed a slightly increased sensitivity to pertuzumab versus parental cells. Neither alpha-IR3 nor pertuzumab decreased HER-2 phosphorylation, suggesting that additional sources of phosphorylation other than IGF-IR exist when HER-2 and IGF-IR are not physically bound. Our data support a unique interaction between HER-2 and IGF-IR in trastuzumab-resistant cells such that cross talk occurs between IGF-IR and HER-2. These data suggest that the IGF-IR/HER-2 heterodimer contributes to trastuzumab resistance and justify the need for further studies examining this complex as a potential therapeutic target in breast cancers that have progressed while on trastuzumab.
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Modulation of levels of p27KIP1 appears to be a common endpoint for several of the resistance pathways noted above, including signaling from IGF-1R and MET.
“Indeed, modulation of levels of p27KIP1 appears to be a common endpoint for several of the resistance pathways noted above, including signaling from IGF-1R and MET (Nahta et al., 2005; Shattuck et al., 2008).”
From ERBB Receptors: From Oncogene Discovery to Basic Science to Mechanism-Based Cancer Therapeutics (2014) · cites this paper as Nahta et al., 2005
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- Authors
- Nahta, R., Yuan, L. X. H., Zhang, B., Kobayashi, R., & Esteva, F. J.
- Affiliations
- 1Breast Medical Oncology, Departments of
- 2Molecular Pathology, and
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Cancer Research
- Published
- 2005-12-01
- Volume
- 65
- Issue
- 23
- Pages
- 11118-11128
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2001447115
- Cited by
- 793
- References
- 25
- Citations by year
- 2026: 15 · 2025: 14 · 2024: 11 · 2023: 42 · 2022: 21 · 2021: 15 · 2020: 20 · 2019: 21 · 2018: 27 · 2017: 36 · 2016: 33 · 2015: 46 · 2014: 48 · 2013: 45 · 2012: 73
- FWCI
- 23.48
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Food and Drug Administration
- Genentech
- National Cancer Institute (K23 CA82119, CA 16672-27, K23CA082119, P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- trastuzumab resistance, HER2, IGF-1 receptor, receptor heterodimerization, breast cancer, IGF-1 signaling, pertuzumab, SK-BR-3 cells
- MeSH terms
- Trastuzumab, Amino Acid Sequence, Antibodies, Monoclonal, Antineoplastic Agents, Breast Neoplasms, Humans, Insulin-Like Growth Factor I, Molecular Sequence Data, Phosphorylation, Receptor, IGF Type 1, Erb-b2 Receptor Tyrosine Kinases, Drug Resistance, Neoplasm, Dimerization, Receptor Cross-Talk, Cell Line, Tumor, Antibodies, Monoclonal, Humanized
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