Better survival with EGFR exon 19 than exon 21 mutations in gefitinib-treated non-small cell lung cancer patients is due to differential inhibition of downstream signals

Abstract Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Our clinical data showed NSCLC patients with exon 19 deletions survived longer following g...

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Bibliographic Details
Published in:Cancer letters 2008-07, Vol.265 (2), p.307-317
Main Authors: Zhu, Jian-quan, Zhong, Wen-zhao, Zhang, Guo-chun, Li, Rong, Zhang, Xu-chao, Guo, Ai-lin, Zhang, Yi-fang, An, She-juan, Mok, Tony S, Wu, Yi-long
Format: Article
Language:English
Subjects:
Adult
Aged
Aged, 80 and over
Autophosphorylation
Cancer therapies
Carcinoma, Non-Small-Cell Lung - genetics
Cell culture
Cell cycle
Cell growth
Cell Line, Tumor
Cell Proliferation - drug effects
Cloning
Epidermal growth factor receptor
Exons
Female
Genes, erbB-1
Hematology, Oncology and Palliative Medicine
Humans
Immunoblotting
Kinases
Lung cancer
Lung Neoplasms
Male
Medical prognosis
Middle Aged
Mutation
Non-small cell lung cancer
Protein Kinase Inhibitors
Quinazolines - pharmacology
Response rates
Retrospective Studies
Rodents
Signal Transduction - drug effects
Studies
Transfection
Tyrosine kinase inhibitor
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Summary:Abstract Somatic mutations in the epidermal growth factor receptor (EGFR) kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with non-small cell lung cancer (NSCLC). Our clinical data showed NSCLC patients with exon 19 deletions survived longer following gefitinib treatment than those with exon 21 point mutations. We aimed to investigate whether these two mutations produced differences in phosphorylation of EGFR and downstream signals. Two stable cell lines expressing these mutations were obtained by transfection. Inhibition of phosphorylation of EGFR, Akt, and Erk by gefitinib was detected using Western blotting, and cell inhibition tests were conducted to evaluate the bio-behavior. Gefitinib inhibited the phosphorylation of EGFR, Akt, and Erk to a greater degree in exon 19 deletion cells than in L858R cells. Gefitinib produced G1 arrest in more of the cells with exon 19 deletion than with L858R. This might be attributable to patient selection in TKIs therapy.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2008.02.064