Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways

Sordella, R., Bell, D. W., Haber, D. A., Settleman, J. (August 2004) Gefitinib-sensitizing EGFR mutations in lung cancer activate anti-apoptotic pathways. Science, 305 (5687). pp. 1163-7. ISSN 1095-9203 (Electronic)

URL: http://www.ncbi.nlm.nih.gov/pubmed/15284455
DOI: 10.1126/science.1101637

Abstract

Gefitinib (Iressa, Astra Zeneca Pharmaceuticals) is a tyrosine kinase inhibitor that targets the epidermal growth factor receptor (EGFR) and induces dramatic clinical responses in nonsmall cell lung cancers (NSCLCs) with activating mutations within the EGFR kinase domain. We report that these mutant EGFRs selectively activate Akt and signal transduction and activator of transcription (STAT) signaling pathways, which promote cell survival, but have no effect on extracellular signal-regulated kinase signaling, which induces proliferation. NSCLC cells expressing mutant EGFRs underwent extensive apoptosis after small interfering RNA-mediated knockdown of the mutant EGFR or treatment with pharmacological inhibitors of Akt and STAT signaling and were relatively resistant to apoptosis induced by conventional chemotherapeutic drugs. Thus, mutant EGFRs selectively transduce survival signals on which NSCLCs become dependent; inhibition of those signals by gefitinib may contribute to the drug's efficacy.

Item Type: Paper
Uncontrolled Keywords: Animals Antineoplastic Agents pharmacology Apoptosis Carcinoma Non-Small Cell Lung drug therapy genetics pathology Catalytic Domain Cell Line Cell Line Tumor Cell Survival DNA-Binding Proteins antagonists & inhibitors metabolism Enzyme Activation Humans Lung Neoplasms drug therapy genetics pathology Mice Milk Proteins Mitogen Activated Protein Kinases metabolism Mutation Mutation Missense Phosphorylation Protein Serine Threonine Kinases antagonists & inhibitors metabolism Proto-Oncogene Proteins antagonists & inhibitors metabolism Proto-Oncogene Proteins c-akt Quinazolines pharmacology RNA, Small Interfering Receptor, Epidermal Growth Factor genetics metabolism STAT5 Transcription Factor Sequence Deletion Signal Transduction Trans-Activators antagonists & inhibitors metabolism Transfection Tyrosine metabolism
Subjects: diseases & disorders > cancer
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 > enzymes > kinase > tyrosine kinase
CSHL Authors:
Communities: CSHL labs > Sordella lab
Depositing User: CSHL Librarian
Date: 20 August 2004
Date Deposited: 09 May 2012 18:35
Last Modified: 04 Mar 2013 14:34
Related URLs:
URI: http://repository.cshl.edu/id/eprint/26247

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