PT  - JOURNAL ARTICLE
AU  - Mitra, Doyel
AU  - Brumlik, Michael J.
AU  - Okamgba, Stella U.
AU  - Zhu, Yun
AU  - Duplessis, Tamika T.
AU  - Parvani, Jenny G.
AU  - Lesko, Samuel M.
AU  - Brogi, Edi
AU  - Jones, Frank E.
TI  - An oncogenic isoform of HER2 associated with locally disseminated breast cancer and trastuzumab resistance
AID  - 10.1158/1535-7163.MCT-09-0295
DP  - 2009 Aug 01
TA  - Molecular Cancer Therapeutics
PG  - 2152--2162
VI  - 8
IP  - 8
4099  - http://mct.aacrjournals.org/content/8/8/2152.short
4100  - http://mct.aacrjournals.org/content/8/8/2152.full
SO  - Mol Cancer Ther2009 Aug 01; 8
AB  - 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. [Mol Cancer Ther 2009;8(8):2152–62]