HER-2 signaling and inhibition in breast cancer.
ABSTRACT Amplification of the HER-2 gene occurs in approximately 25% of breast cancers, causing up-regulation of key signaling pathways which control cell growth and survival. In breast cancer patients, HER-2 overexpression correlates with an aggressive phenotype and poor prognosis. HER-2, therefore, has become the focus of many anti-cancer therapeutic approaches. Trastuzumab (Herceptin), a humanized monoclonal antibody directed against the extracellular domain of HER-2, was the first FDA-approved HER-2-targeted therapy for the treatment of metastatic breast cancer. However, not all HER-2-overexpressing patients respond to trastuzumab and most that initially respond develop resistance within one year of treatment. Trastuzumab resistance has been studied in cell line models of resistance and several mechanisms of resistance have been proposed. More recent anti-HER-2 strategies involve targeting its tyrosine kinase domain; for example, lapatinib (Tykerb) is a dual HER-2 and EGFR tyrosine kinase inhibitor and has shown efficacy as a single agent and in combination with other therapeutics. A number of novel HER-2 antagonists are currently in preclinical or clinical development, including both monoclonal antibodies and small molecule inhibitors. Increased understanding of HER-2 signaling in breast cancer, and of response and resistance to HER-2 antagonists, will aid the development of strategies to overcome resistance to HER-2 targeted therapies.
- SourceAvailable from: Per Eystein Lønning[Show abstract] [Hide abstract]
ABSTRACT: Chemoresistance remains the main reason for therapeutic failure in breast cancer as well as most other solid tumours. While gene expression profiles related to prognosis have been developed, so far use of such signatures as well as single markers has been of limited value predicting drug resistance. Novel technologies, in particular with regard to high through-put sequencing holds great promises for future identification of the key "driver" mechanisms guiding chemosensitivity versus resistance in breast cancer as well as other malignant conditions.Molecular oncology 04/2010; 4(3):284-300. DOI:10.1016/j.molonc.2010.04.005 · 5.94 Impact Factor
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ABSTRACT: The advent of cancer stem cell (CSC) hypothesis has revolutionized the cancer biology community's thinking in explaining the notorious resistance of cancer to conventional chemo- and radiotherapies. The hypothesis states that the CSCs are a subpopulation within the tumor endowed with superior resistance and with the exclusive ability to self-renew, differentiate into diverse type of progeny cancer cells, and initiate tumor. Here, we review recent literature that seek out to explain such resistance of CSCs. Signaling pathways involved in the regulation of proliferation and differentiation of stem cells (e.g. Notch, Hh, and Wnt) and efficient ABC transporter systems and DNA damage response machineries are starting to be identified as the means by which CSCs out-survive their non-CSC neighbors after conventional anti-cancer treatments. Direct links between receptor tyrosine kinase pathways and CSCs are also starting to emerge as well. Lastly, a promising relationship between epithelial-mesenchymal transition and CSCs is discussed. Though the precise resistance pathway of CSCs is not yet fully elucidated, the various mechanisms highlighted here provide promise for better fundamental understanding of CSCs and the subsequent development of a more effective CSC-targeting therapeutic in the foreseeable future.05/2009; 2(2):109-114. DOI:10.15283/ijsc.2009.2.2.109