Cited by 793HER2/EGFR in Cancer ResearchGrowth Hormone and Insulin-like Growth FactorsLung Cancer Treatments and Mutations

Insulin-like growth factor-I receptor/human epidermal growth factor receptor 2 heterodimerization contributes to trastuzumab resistance of breast cancer cells

Nahta, Rita, Yuan, Linda X.H., Zhang, Bing, Kobayashi, Ryuji, Esteva, Francisco J.·2005·Cancer Research

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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Crossref · 10.1158/0008-5472.can-04-3841

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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).”

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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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