Pharmacological strategies to overcome HER2 cross-talk and Trastuzumab resistance.
Approximately 20-30% of breast cancers show increased expression of the HER2 receptor tyrosine kinase. Trastuzumab (Herceptin) is a clinically approved anti-HER2 monoclonal antibody. Many patients with HER2-overexpressing metastatic breast cancer respond to trastuzumab; however, a subset display primary drug resistance. In addition, many patients who initially respond to trastuzumab ultimately develop disease progression. Multiple molecular mechanisms contributing to trastuzumab resistance have been proposed in the literature. These mechanisms include cross-signaling from related HER/erbB receptors and compensatory signaling from receptors outside of the HER/erbB family, including receptors for insulin-like growth factor-I, vascular endothelial growth factor, and transforming growth factor beta. The major downstream signaling pathway activated by HER2 cross-talk is PI3K/mTOR, and a potential integrator of receptor cross-talk is Src-focal adhesion kinase (FAK) signaling. PI3K, Src, and FAK have independently been implicated in trastuzumab resistance. In this review, we will discuss pharmacological inhibition of HER2 cross-talk as a strategy to treat trastuzumab-refractory HER2-overexpresssing breast cancer.
Departments of Pharmacology, Emory University School of Medicine, USA. rnahta@emory.edu
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D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy*; D002626:Chemistry, Pharmaceutical; D019281:Dimerization; D015195:Drug Design; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D005260:Female; D006801:Humans; D020239:Receptor Cross-Talk / Q000187:drug effects*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D020893:Receptor, ErbB-3 / Q000378:metabolism; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab