HER receptor signaling confers resistance to the insulin-like growth factor 1 receptor inhibitor, BMS-536924
| Autor: | Haluska, Paul, Carboni, Joan M., Eyck, Cynthia Ten, Attar, Ricardo M., Hou, Xiaonan, Yu, Chunrong, Sagar, Malvika, Wong, Tai W., Gottardis, Marco M., Erlichman, Charles |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Ovarian Neoplasms
Cell Death Pyridones Receptor ErbB-2 Antineoplastic Agents Drug Synergism Receptor Cross-Talk Article Receptor Insulin Receptor IGF Type 1 Enzyme Activation Drug Resistance Neoplasm Cell Line Tumor Humans Benzimidazoles Female Drug Screening Assays Antitumor Phosphorylation Extracellular Signal-Regulated MAP Kinases Protein Kinase Inhibitors Proto-Oncogene Proteins c-akt Cell Proliferation Signal Transduction |
| Popis: | We have reported previously the activity of the insulin-like growth factor-I (IGF-IR)/insulin receptor (InsR) inhibitor, BMS-554417, in breast and ovarian cancer cell lines. Further studies indicated treatment of OV202 ovarian cancer cells with BMS-554417 increased phosphorylation of HER-2. In addition, treatment with the pan-HER inhibitor, BMS-599626, resulted in increased phosphorylation of IGF-IR, suggesting a reciprocal cross-talk mechanism. In a panel of five ovarian cancer cell lines, simultaneous treatment with the IGF-IR/InsR inhibitor, BMS-536924 and BMS-599626, resulted in a synergistic antiproliferative effect. Furthermore, combination therapy decreased AKT and extracellular signal-regulated kinase activation and increased biochemical and nuclear morphologic changes consistent with apoptosis compared with either agent alone. In response to treatment with BMS-536924, increased expression and activation of various members of the HER family of receptors were seen in all five ovarian cancer cell lines, suggesting that inhibition of IGF-IR/InsR results in adaptive up-regulation of the HER pathway. Using MCF-7 breast cancer cell variants that overexpressed HER-1 or HER-2, we then tested the hypothesis that HER receptor expression is sufficient to confer resistance to IGF-IR-targeted therapy. In the presence of activating ligands epidermal growth factor or heregulin, respectively, MCF-7 cells expressing HER-1 or HER-2 were resistant to BMS-536924 as determined in a proliferation and clonogenic assay. These data suggested that simultaneous treatment with inhibitors of the IGF-I and HER family of receptors may be an effective strategy for clinical investigations of IGF-IR inhibitors in breast and ovarian cancer and that targeting HER-1 and HER-2 may overcome clinical resistance to IGF-IR inhibitors. |
| Databáze: | OpenAIRE |
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