title: 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.
authors.affiliation: Department of Breast Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030-4009, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Nahta
authors.forename: Linda X H
authors.initials: LX
authors.lastname: Yuan
authors.forename: Bing
authors.initials: B
authors.lastname: Zhang
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kobayashi
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Esteva
mesh_terms: D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D019281:Dimerization; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000494:pharmacology; D008969:Molecular Sequence Data; D010766:Phosphorylation; D020239:Receptor Cross-Talk; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology / Q000378:metabolism*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D007334:Insulin-Like Growth Factor I; D018719:Erb-b2 Receptor Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000068878:Trastuzumab; C485206:pertuzumab