| Acquired resistance to EGFR tyrosine kinase inhibitors in cancer cells is mediated by loss of IGF-binding proteins. | |
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MedLine Citation:
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PMID: 18568074 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Although some cancers are initially sensitive to EGFR tyrosine kinase inhibitors (TKIs), resistance invariably develops. We investigated mechanisms of acquired resistance to the EGFR TKI gefitinib by generating gefitinib-resistant (GR) A431 squamous cancer cells. In GR cells, gefitinib reduced phosphorylation of EGFR, ErbB-3, and Erk but not Akt. These cells also showed hyperphosphorylation of the IGFI receptor (IGFIR) and constitutive association of IRS-1 with PI3K. Inhibition of IGFIR signaling disrupted the association of IRS-1 with PI3K and restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit GR cell growth. Gene expression analyses revealed that GR cells exhibited markedly reduced IGF-binding protein 3 (IGFBP-3) and IGFBP-4 RNA. Addition of recombinant IGFBP-3 restored the ability of gefitinib to downregulate PI3K/Akt signaling and to inhibit cell growth. Finally, gefitinib treatment of mice with A431 xenografts in combination with an IGFIR-specific monoclonal antibody prevented tumor recurrence, whereas each drug given alone was unable to do so. These data suggest that loss of expression of IGFBPs in tumor cells treated with EGFR TKIs derepresses IGFIR signaling, which in turn mediates resistance to EGFR antagonists. Moreover, combined therapeutic inhibition of EGFR and IGFIR may abrogate this acquired mechanism of drug resistance and is thus worthy of prospective clinical investigation. |
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Authors:
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Marta Guix; Anthony C Faber; Shizhen Emily Wang; Maria Graciela Olivares; Youngchul Song; Sherman Qu; Cammie Rinehart; Brenda Seidel; Douglas Yee; Carlos L Arteaga; Jeffrey A Engelman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 118 ISSN: 0021-9738 ISO Abbreviation: J. Clin. Invest. Publication Date: 2008 Jul |
Date Detail:
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Created Date: 2008-07-03 Completed Date: 2008-09-25 Revised Date: 2013-06-03 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 2609-19 Citation Subset: AIM; IM |
Affiliation:
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Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-6307, USA. |
Export Citation:
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APA/MLA Format Download EndNote Download BibTex |
| MeSH Terms | |
Descriptor/Qualifier:
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Adaptor Proteins, Signal Transducing
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metabolism Animals Carcinoma, Squamous Cell / drug therapy, pathology Cell Line, Tumor Cell Survival / drug effects Drug Resistance, Neoplasm* Female Gene Expression / drug effects Humans Insulin Receptor Substrate Proteins Insulin-Like Growth Factor Binding Protein 3 / genetics, metabolism Insulin-Like Growth Factor Binding Protein 4 / genetics, metabolism Insulin-Like Growth Factor Binding Proteins / genetics, metabolism* Insulin-Like Growth Factor I / metabolism, pharmacology Insulin-Like Growth Factor II / metabolism Mice Mice, Nude Phosphatidylinositol 3-Kinases / antagonists & inhibitors, metabolism Phosphorylation / drug effects Protein Kinase Inhibitors / pharmacology*, therapeutic use Proto-Oncogene Proteins c-akt / metabolism Quinazolines / pharmacology, therapeutic use Receptor, Epidermal Growth Factor / antagonists & inhibitors* Receptor, IGF Type 1 / antagonists & inhibitors, metabolism Receptor, erbB-3 / metabolism Xenograft Model Antitumor Assays |
| Grant Support | |
ID/Acronym/Agency:
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K08 CA120060-01/CA/NCI NIH HHS; P30 CA68485/CA/NCI NIH HHS; P50 CA127003/CA/NCI NIH HHS; P50 CA98131/CA/NCI NIH HHS; R00 CA125892-06/CA/NCI NIH HHS; R01 CA80195/CA/NCI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Adaptor Proteins, Signal Transducing; 0/IRS1 protein, human; 0/Insulin Receptor Substrate Proteins; 0/Insulin-Like Growth Factor Binding Protein 3; 0/Insulin-Like Growth Factor Binding Protein 4; 0/Insulin-Like Growth Factor Binding Proteins; 0/Irs1 protein, mouse; 0/Protein Kinase Inhibitors; 0/Quinazolines; 67763-96-6/Insulin-Like Growth Factor I; 67763-97-7/Insulin-Like Growth Factor II; EC 2.7.1.-/Phosphatidylinositol 3-Kinases; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 2.7.10.1/Receptor, IGF Type 1; EC 2.7.10.1/Receptor, erbB-3; EC 2.7.11.1/Proto-Oncogene Proteins c-akt; S65743JHBS/gefitinib |
| Comments/Corrections | |
Comment In:
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J Clin Invest. 2008 Jul;118(7):2389-92
[PMID:
18568082
]
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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