Abstract
Lapatinib-resistance is a major problem for HER2-positive breast cancer treatment. SK-BR-3-LR, a lapatinib-resistant cell clone, was established from HER2-positive SK-BR-3 breast cancer cells following chronic exposure to lapatinib. The PI3K/AKT signaling pathway was demonstrated to be resistant to HER2 inhibition in SK-BR-3-LR cells. However, both small-molecular Recepteur d'Origine Nantais (RON) inhibitors and RON-targeted small interfering RNA (siRNA) effectively restored lapatinib sensitivity in these cells by inhibiting PI3K/AKT activation. Our results demonstrate for the first time the important role of RON in mediating lapatinib resistance and suggest that RON-targeted therapy may become a novel, promising therapeutic strategy after the failure of lapatinib treatment in patients with HER2-positive breast cancer.
Keywords:
HER2; HER2-targeted agents; Lapatinib resistance; RON.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Anilides / pharmacology
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Antibodies, Monoclonal, Humanized / pharmacology
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Antineoplastic Agents / pharmacology*
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Breast Neoplasms
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Cell Line, Tumor
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Cell Proliferation / drug effects
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Crizotinib
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Drug Resistance, Neoplasm
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Drug Screening Assays, Antitumor
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Female
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Gene Knockdown Techniques
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Humans
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Inhibitory Concentration 50
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Lapatinib
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism
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Pyrazoles / pharmacology
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Pyridines / pharmacology
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Quinazolines / pharmacology*
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Quinolines / pharmacology
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Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
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Receptor Protein-Tyrosine Kinases / genetics
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Receptor Protein-Tyrosine Kinases / metabolism*
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Receptor, ErbB-2 / metabolism*
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Signal Transduction
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Trastuzumab
Substances
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Anilides
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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GSK 1363089
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Pyrazoles
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Pyridines
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Quinazolines
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Quinolines
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Lapatinib
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Crizotinib
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Phosphatidylinositol 3-Kinases
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ERBB2 protein, human
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RON protein
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Receptor Protein-Tyrosine Kinases
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Receptor, ErbB-2
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Proto-Oncogene Proteins c-akt
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Trastuzumab