Abstract
Herceptin (trastuzumab) is the backbone of HER2-directed breast cancer therapy and benefits patients in both the adjuvant and metastatic settings. Here, we describe a mechanism of action for trastuzumab whereby antibody treatment disrupts ligand-independent HER2/HER3 interactions in HER2-amplified cells. The kinetics of dissociation parallels HER3 dephosphorylation and uncoupling from PI3K activity, leading to downregulation of proximal and distal AKT signaling, and correlates with the antiproliferative effects of trastuzumab. A selective and potent PI3K inhibitor, GDC-0941, is highly efficacious both in combination with trastuzumab and in the treatment of trastuzumab-resistant cells and tumors.
MeSH terms
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Animals
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Antibodies, Monoclonal / pharmacology*
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / drug therapy*
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Breast Neoplasms / metabolism
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Cell Line, Tumor
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Drug Resistance, Neoplasm / genetics
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Female
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Humans
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Indazoles / pharmacology*
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Ligands
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Mutation
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Phosphatidylinositol 3-Kinases / genetics
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Phosphoinositide-3 Kinase Inhibitors*
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Proto-Oncogene Proteins c-akt / metabolism
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Receptor, ErbB-2 / antagonists & inhibitors
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Receptor, ErbB-2 / metabolism
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Receptor, ErbB-3 / antagonists & inhibitors
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Receptor, ErbB-3 / metabolism
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Signal Transduction / drug effects
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Sulfonamides / pharmacology*
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Trastuzumab
Substances
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Indazoles
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Ligands
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Phosphoinositide-3 Kinase Inhibitors
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Sulfonamides
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Receptor, ErbB-2
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Receptor, ErbB-3
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Proto-Oncogene Proteins c-akt
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Trastuzumab