Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib

Kwak, E. L., Sordella, R., Bell, D. W., Godin-Heymann, N., Okimoto, R. A., Brannigan, B. W., Harris, P. L., Driscoll, D. R., Fidias, P., Lynch, T. J., Rabindran, S. K., McGinnis, J. P., Wissner, A., Sharma, S. V., Isselbacher, K. J., Settleman, J., Haber, D. A. (May 2005) Irreversible inhibitors of the EGF receptor may circumvent acquired resistance to gefitinib. Proceedings of the National Academy of Sciences of the United States of America, 102 (21). pp. 7665-70. ISSN 0027-8424

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URL: http://www.ncbi.nlm.nih.gov/pubmed/15897464
DOI: 10.1073/pnas.0502860102

Abstract

Non-small cell lung cancers (NSCLCs) with activating mutations in the kinase domain of the epidermal growth factor receptor (EGFR) demonstrate dramatic, but transient, responses to the reversible tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva). Some recurrent tumors have a common secondary mutation in the EGFR kinase domain, T790M, conferring drug resistance, but in other cases the mechanism underlying acquired resistance is unknown. In studying multiple sites of recurrent NSCLCs, we detected T790M in only a small percentage of tumor cells. To identify additional mechanisms of acquired resistance to gefitinib, we used NSCLC cells harboring an activating EGFR mutation to generate multiple resistant clones in vitro. These drug-resistant cells demonstrate continued dependence on EGFR and ERBB2 signaling for their viability and have not acquired secondary EGFR mutations. However, they display increased internalization of ligand-activated EGFR, consistent with altered receptor trafficking. Although gefitinib-resistant clones are cross-resistant to related anilinoquinazolines, they demonstrate sensitivity to a class of irreversible inhibitors of EGFR. These inhibitors also show effective inhibition of signaling by T790M-mutant EGFR and killing of NSCLC cells with the T790M mutation. Both mechanisms of gefitinib resistance are therefore circumvented by irreversible tyrosine kinase inhibitors. Our findings suggest that one of these, HKI-272, may prove highly effective in the treatment of EGFR-mutant NSCLCs, including tumors that have become resistant to gefitinib or erlotinib.

Item Type: Paper
Uncontrolled Keywords: Aminoquinolines Aniline Compounds Base Sequence Carcinoma Non Small Cell Lung genetics metabolism Cell Proliferation drug effects Drug Resistance genetics Humans Immunoblotting Lung Neoplasms genetics metabolism Molecular Sequence Data Mutation genetics Neoplasm Recurrence Local genetics metabolism Organic Chemicals pharmacology Phosphorylation drug effects Quinazolines metabolism Quinolines pharmacology Receptor, Epidermal Growth Factor antagonists & inhibitors genetics physiology Receptor erbB-2 physiology Sequence Analysis DNA Signal Transduction drug effects physiology Tumor Cells Cultured
Subjects: diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
diseases & disorders > cancer > cancer types > lung cancer
CSHL Authors:
Communities: CSHL labs > Sordella lab
Depositing User: CSHL Librarian
Date: 24 May 2005
Date Deposited: 24 Apr 2012 17:44
Last Modified: 11 Jan 2018 19:51
PMCID: PMC1129023
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26252

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