| Abstract: |
The HER2-targeted therapy trastuzumab is widely used for the treatment of patients with metastatic breast tumors overexpressing HER2. However, an objective response is observed in only 12% to 24% of patients treated with trastuzumab as a single agent and initial responders regress in < 6 months (1-3). The reason for the clinical failure of trastuzumab in this setting remains unclear. Here we show that local lymph node-positive disease progression in 89% of breast cancer patients with HER2-positive tumors involves the HER2 oncogenic variant HER2Δ16. We further show that ectopic expression of HER2Δ16, but not wild-type HER2, promotes receptor dimerization, cell invasion, and trastuzumab resistance of NIH3T3 and MCF-7 tumor cell lines. The potentiated metastatic and oncogenic properties of HER2Δ16 were mediated through direct coupling of HER2Δ16 to Src kinase. Cotargeting of HER2Δ16 and Src kinase with the single-agent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, destabilization of HER2Δ16, and suppressed tumorigenicity. Activated Src kinase was also observed in 44% of HER2Δ16-expressing breast carcinomas underscoring the potential clinical implications of coupled HER2Δ16 and Src signaling. Our results suggest that HER2Δ16 expression is an important genetic event driving trastuzumab-refractory breast cancer. We propose that successful targeted therapeutics for intervention of aggressive HER2-positive breast cancers will require a strategy to suppress HER2Δ16 oncogenic signaling. One possibility involves a therapeutic strategy employing single-agent tyrosine kinase inhibitors to disengage the functionally coupled oncogenic HER2Δ16 and Src tyrosine kinase pathways. Copyright © 2009 American Association for Cancer Research. |
| Keywords: |
signal transduction; controlled study; human tissue; protein expression; unclassified drug; human cell; nonhuman; antineoplastic agents; lymph node metastasis; animal cell; mouse; animals; mice; breast cancer; epidermal growth factor receptor 2; drug effect; drug resistance, neoplasm; cell line, tumor; transfection; dasatinib; protein tyrosine kinase; breast neoplasms; cancer invasion; fluorescent antibody technique; gene expression regulation, neoplastic; antibodies, monoclonal; dimerization; receptor, erbb-2; trastuzumab; cell strain mcf 7; protein isoforms; cell strain 3t3; nih 3t3 cells; epidermal growth factor receptor 2delta16
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