HER2 therapy. Small molecule HER-2 tyrosine kinase inhibitors
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* Corresponding author: Neil Spector Neil.Spector@duke.edu
1 Department of Medicine, Division of Hematology/Oncology, Duke Comprehensive Cancer Center, Duke University Medical Center, Research Drive, Durham, North Carolina 27709, USA
2 Oncology Medicine Development Center, GlaxoSmithKline, Greenford Road, Middlesex UB6 OHE, Greenford, UK
3 Weizmann Institute of Research, P.O. Box 26, Rehovot 76100, Israel
4 Targeted Molecular Diagnostics, Oakmont Lane, Westmont, Illinois 60559, USA
Breast Cancer Research 2007, 9:205 doi:10.1186/bcr1652
Published: 2 March 2007Abstract
Overexpression of the human epidermal growth factor receptor (HER)-2 oncogenic receptor tyrosine kinase, which occurs in 25% of breast cancers, portends poor clinical outcome and consequently represents an attractive target for therapeutic intervention. Small molecule tyrosine kinase inhibitors that compete with ATP binding at the cytoplasmic catalytic kinase domain of HER-2 block autophosphorylation and activation of HER-2, resulting in inhibition of downstream proliferation and survival signals. These agents have exhibited clinical activity in patients with HER-2 overexpressing breast cancers. Here we review the development of HER-2 tyrosine kinase inhibitors, their mechanisms of action, their biological and clinical activities, their safety profile, and combination strategies including conventional cytotoxics and other targeted agents.