Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib

Mulloy, R., Ferrand, A., Kim, Y., Sordella, R., Bell, D. W., Haber, D. A., Anderson, K. S., Settleman, J. (March 2007) Epidermal growth factor receptor mutants from human lung cancers exhibit enhanced catalytic activity and increased sensitivity to gefitinib. Cancer Research, 67 (5). pp. 2325-30. ISSN 0008-5472

URL: http://www.ncbi.nlm.nih.gov/pubmed/17332364
DOI: 10.1158/0008-5472.CAN-06-4293

Abstract

Somatic mutations within the epidermal growth factor receptor (EGFR) kinase domain are detected in 10% to 30% of human non-small cell lung cancers and are correlated with striking clinical responses in a subset of patients treated with EGFR kinase inhibitors, such as gefitinib and erlotinib. Cell-based studies suggest that these mutant EGFRs promote increased autophosphorylating activity on a subset of EGFR COOH-terminal tyrosines and the consequent engagement of a subset of downstream effectors. Because EGFR function is regulated at multiple levels in vivo, and it is therefore difficult to assess the direct consequences of these mutations on EGFR enzyme function, we measured EGFR catalytic activity in in vitro kinase assays using purified recombinant proteins corresponding to the cytoplasmic domain of wild-type and two frequently detected EGFR mutants (DelL747-P753insS and L858R). Both mutants exhibit substantially increased autophosphorylating activity relative to wild-type EGFR, and they exhibit distinct reaction kinetics. In addition, the mutant kinases are more sensitive to kinase inhibition by gefitinib, which seems to reflect their increased drug affinity. These findings suggest that the altered signaling properties and drug sensitivity of these EGFR mutants that have been observed in vivo largely result from differences in the catalytic properties of the kinase. In addition, we find that the T790M secondary "drug resistance mutation" of EGFR, which frequently arises in relapsed patients that initially responded to treatment, confers enhanced kinase activity to primary activating EGFR alleles and may, therefore, be oncogenic in some contexts.

Item Type: Paper
Uncontrolled Keywords: Animals Antineoplastic Agents/pharmacology Baculoviridae/genetics Catalysis/drug effects Cells, Cultured Drug Resistance, Neoplasm/genetics Humans Lung Neoplasms/enzymology/ genetics Mutant Proteins/isolation & purification Phosphotransferases/metabolism Quinazolines/ pharmacology Receptor, Epidermal Growth Factor/ antagonists & inhibitors/ genetics/isolation & purification/metabolism Spodoptera Substrate Specificity
Subjects: diseases & disorders > cancer
diseases & disorders
bioinformatics > genomics and proteomics > genetics & nucleic acid processing
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification
diseases & disorders > cancer > drugs and therapies > chemotherapy
diseases & disorders > cancer > drugs and therapies
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > EGFR
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > epidermal growth factor
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > enzymes > kinase
diseases & disorders > cancer > cancer types > lung cancer
bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types
CSHL Authors:
Communities: CSHL labs > Sordella lab
Depositing User: CSHL Librarian
Date: 1 March 2007
Date Deposited: 10 Nov 2011 15:15
Last Modified: 13 Mar 2013 15:51
Related URLs:
URI: http://repository.cshl.edu/id/eprint/23102

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