Abstract
Inherent and acquired resistance to targeted therapeutics continues to emerge as a major clinical obstacle. For example, resistance to EGF receptor targeting occurs commonly, more so than was expected, on the basis of preclinical work. Given emerging evidence that cancer cell-substrate interactions are important determinants of therapeutic sensitivity, we examined the impact of cell-fibronectin interactions on the efficacy of the EGF receptor antibody cetuximab, which is used widely for lung cancer treatment. Our results revealed the potential for cell-fibronectin interactions to induce radioresistance of human non-small cell lung cancer cells. Cell adhesion to fibronectin enhanced tumor cell radioresistance and attenuated the cytotoxic and radiosensitizing effects of cetuximab. Both in vitro and in vivo, we found that cetuximab treatment led to a remarkable induction of fibronectin biosynthesis. Mechanistic analyses revealed the induction was mediated by a p38-MAPK-ATF2 signaling pathway and that RNAi-mediated inhibition of fibronectin could elevate the cytotoxic and radiosensitizing potential of cetuximab. Taken together, our findings show how cell adhesion blunts cetuximab, which, by inducing fibronectin, generates a self-attenuating mechanism of drug resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Monoclonal, Humanized / pharmacology*
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects*
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Apoptosis / radiation effects
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Blotting, Western
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Carcinoma, Non-Small-Cell Lung / genetics
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Carcinoma, Non-Small-Cell Lung / metabolism
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Carcinoma, Non-Small-Cell Lung / pathology*
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Cell Adhesion / drug effects
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Cell Adhesion / radiation effects
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Cell Cycle / drug effects
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Cell Cycle / radiation effects
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Movement / radiation effects
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Cell Proliferation / drug effects
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Cell Proliferation / radiation effects
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Cetuximab
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Drug Resistance, Neoplasm
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ErbB Receptors / antagonists & inhibitors
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ErbB Receptors / genetics
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ErbB Receptors / metabolism*
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Female
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Fibronectins / metabolism*
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Fluorescent Antibody Technique
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Humans
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Immunoenzyme Techniques
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Immunoprecipitation
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Lung Neoplasms / genetics
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Lung Neoplasms / metabolism
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Lung Neoplasms / pathology*
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Male
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Mice
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Mice, Nude
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Mitogen-Activated Protein Kinase 8 / genetics
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Mitogen-Activated Protein Kinase 8 / metabolism
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Phosphorylation
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RNA, Messenger / genetics
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Radiation-Sensitizing Agents / pharmacology*
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Real-Time Polymerase Chain Reaction
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction
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X-Rays
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p38 Mitogen-Activated Protein Kinases / genetics
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Fibronectins
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RNA, Messenger
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Radiation-Sensitizing Agents
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ErbB Receptors
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Mitogen-Activated Protein Kinase 8
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p38 Mitogen-Activated Protein Kinases
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Cetuximab