Abstract
L755S, a HER2 kinase domain mutation, is the most common HER2 mutation in breast cancer associated with resistance to anti-HER2 trastuzumab treatment. Here, we showed that HER2-L755S confers hyperactivation of MAPK and PI3K/AKT/mTOR pathways and resistance to both reversible and irreversible HER2 tyrosine kinase inhibitors. We further demonstrated that the HER2 TKIs in combination with MEK inhibitor, AZD6244, or PI3K inhibitor, GDC0941, yield robust killing in HER2-L755S cancer cells, indicating a novel targeted strategy to overcome HER2-L755S resistance to anti-HER2 treatment.
Keywords:
HER2; L755S; combination; lapatinib; neratinib; resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Antineoplastic Agents / pharmacology
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Breast Neoplasms / drug therapy
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Breast Neoplasms / genetics
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Cell Line, Tumor
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Drug Resistance, Neoplasm / drug effects*
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Drug Resistance, Neoplasm / genetics
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Female
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Humans
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Mitogen-Activated Protein Kinases / genetics*
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Mutation / drug effects
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Mutation / genetics*
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Phosphatidylinositol 3-Kinases / genetics*
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Protein Kinase Inhibitors / pharmacology*
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Receptor, ErbB-2 / genetics*
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Signal Transduction / drug effects
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Signal Transduction / genetics
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TOR Serine-Threonine Kinases / genetics*
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Trastuzumab / pharmacology
Substances
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Antineoplastic Agents
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Protein Kinase Inhibitors
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MTOR protein, human
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ERBB2 protein, human
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Receptor, ErbB-2
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TOR Serine-Threonine Kinases
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Mitogen-Activated Protein Kinases
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Trastuzumab