Abstract
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.
Keywords: Breast cancer, erbB2, Her2, Herceptin, resistance, Trastuzumab, cross-talk, lapatinib, pertuzumab, IGF-IR, VEGF, TGF beta, FAK
Current Medicinal Chemistry
Title: Pharmacological Strategies to Overcome HER2 Cross-Talk and Trastuzumab Resistance
Volume: 19 Issue: 7
Author(s): R. Nahta
Affiliation:
Keywords: Breast cancer, erbB2, Her2, Herceptin, resistance, Trastuzumab, cross-talk, lapatinib, pertuzumab, IGF-IR, VEGF, TGF beta, FAK
Abstract: 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.
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Cite this article as:
Nahta R., Pharmacological Strategies to Overcome HER2 Cross-Talk and Trastuzumab Resistance, Current Medicinal Chemistry 2012; 19 (7) . https://dx.doi.org/10.2174/092986712799320691
DOI https://dx.doi.org/10.2174/092986712799320691 |
Print ISSN 0929-8673 |
Publisher Name Bentham Science Publisher |
Online ISSN 1875-533X |
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