Abstract
Trastuzumab (Herceptin(®)) is currently used as a treatment for patients whose breast tumors overexpress HER2/ErbB2. Trastuzumab-DM1 (T-DM1, trastuzumab emtansine) is designed to combine the clinical benefits of trastuzumab with a potent microtubule-disrupting drug, DM1 (a maytansine derivative). Currently T-DM1 is being tested in multiple clinical trials. The mechanisms of action for trastuzumab include inhibition of PI3K/AKT signaling pathway, inhibition of HER-2 shedding and Fcγ receptor mediated engagement of immune cells, which may result in antibody-dependent cellular cytotoxicity (ADCC). Here we report that T-DM1 retains the mechanisms of action of unconjugated trastuzumab and is active against lapatinib resistant cell lines and tumors.
MeSH terms
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Ado-Trastuzumab Emtansine
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Animals
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Antibodies, Monoclonal / therapeutic use*
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Antibodies, Monoclonal, Humanized
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Antibody-Dependent Cell Cytotoxicity / drug effects
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Blotting, Western
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Breast Neoplasms / pathology
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Cell Line, Tumor
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Cell Survival / drug effects
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Drug Resistance, Neoplasm / drug effects*
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Female
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Humans
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Immunoconjugates
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Immunotoxins / therapeutic use*
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Lapatinib
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Maytansine / analogs & derivatives*
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Maytansine / therapeutic use
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Mice
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Mice, Nude
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Mice, Transgenic
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Phosphatidylinositol 3-Kinases / metabolism
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Quinazolines / adverse effects*
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Receptor, ErbB-2 / antagonists & inhibitors*
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Receptor, ErbB-2 / immunology
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Receptor, ErbB-2 / metabolism
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Signal Transduction / drug effects
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Trastuzumab
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Immunoconjugates
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Immunotoxins
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Quinazolines
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Lapatinib
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Maytansine
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ERBB2 protein, human
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Receptor, ErbB-2
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Trastuzumab
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Ado-Trastuzumab Emtansine