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1 Department of Medical Oncology and Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute; 2 Department of Medicine, Brigham and Women's Hospital and Harvard Medical School; 3 Department of Pathology, Harvard Medical School, Boston, Massachusetts; and 4 The Broad Institute of MIT and Harvard, Cambridge, Massachusetts
Requests for reprints: Kwok-Kin Wong, Department of Medical Oncology and Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Dana 810B, 44 Binney Street, Boston, MA 02115. Phone: 617-632-6084; Fax: 617-582-7839; E-mail: kwong1{at}partners.org and Geoffrey I. Shapiro, Department of Medical Oncology and Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Dana 810A, 44 Binney Street, Boston, MA 02115. Phone: 617-632-4942; Fax: 617-632-1977; E-mail: geoffrey_shapiro{at}dfci.harvard.edu.
Mutation-specific cancer therapy has shown promising clinical efficacy. In non–small-cell lung cancer (NSCLC), the presence of mutations in the epidermal growth factor receptor (EGFR) tyrosine kinase correlates with clinical response to small-molecule tyrosine kinase inhibitors. Here, we show that cells harboring the G776insV_G/C mutation in the related ERBB2 tyrosine kinase (also known as HER2 or Neu), present in a small percentage of NSCLCs, are sensitive to HKI-272, an irreversible dual-specific kinase inhibitor targeting both EGFR and ERBB2. In the ERBB2-mutant NCI-H1781 cell line, HKI-272 treatment inhibited proliferation by induction of G1 arrest and apoptotic cell death. Furthermore, HKI-272 abrogated autophosphorylation of both ERBB2 and EGFR. Finally, Ba/F3 murine pro-B cells, engineered to express mutant ERBB2, became independent of interleukin-3 and sensitive to HKI-272. Thus, the subset of NSCLC patients with tumors carrying the ERBB2 G776insV_G/C mutation may benefit from treatment with HKI-272. (Cancer Res 2006; 66(13): 6487-91)
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