Data from An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance

Abstract

<div>Abstract<p>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 (<a href="#bib1" target="_blank">1</a>–<a href="#bib3" target="_blank">3</a>). 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. [Mol Cancer Ther 2009;8(8):2152–62]</p></div>