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 HER2Delta16. We further show that ectopic expression of HER2Delta16, 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 HER2Delta16 were mediated through direct coupling of HER2Delta16 to Src kinase. Cotargeting of HER2Delta16 and Src kinase with the single-agent tyrosine kinase inhibitor dasatinib resulted in Src inactivation, destabilization of HER2Delta16, and suppressed tumorigenicity. Activated Src kinase was also observed in 44% of HER2Delta16-expressing breast carcinomas underscoring the potential clinical implications of coupled HER2Delta16 and Src signaling. Our results suggest that HER2Delta16 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 HER2Delta16 oncogenic signaling. One possibility involves a therapeutic strategy employing single-agent tyrosine kinase inhibitors to disengage the functionally coupled oncogenic HER2Delta16 and Src tyrosine kinase pathways.
Highlights
Recent human tumor gene expression profiling initiatives have resulted in the identification of five distinct breast cancer phenotypic subclasses underscoring the complexity of this disease [4,5,6]
Clinical validation of the breast tumor gene expression classification scheme showed that each tumor subclass exhibited distinct clinical outcomes with the HER2/ ErbB2/neu (HER2)–positive subtype associated with the shortest relapse-free and overall patient survival [6, 7]
HER2Δ16 appears to be a tumor-specific HER2 oncogenic isoform coexpressed with HER2 in nearly half of the HER2-positive invasive breast tumors analyzed in this study
Summary
Recent human tumor gene expression profiling initiatives have resulted in the identification of five distinct breast cancer phenotypic subclasses underscoring the complexity of this disease [4,5,6]. The vast majority of patients exhibit de novo resistance to single-agent trastuzumab with an objective response observed in only 12% to 24% of patients with HER2-positive tumors and all initial responders develop resistance in
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