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Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants

Oncogene volume 25, pages 1205–1215 (2006)Cite this article

Abstract

Mutations in the kinase domain of epidermal growth factor receptor (EGFR) are associated with clinical responsiveness to gefitinib in patients with non-small-cell lung cancers (NSCLC). Recently, we have identified many novel EGFR mutations in NSCLC tissues. In this study, we found that gefitinib could suppress the tyrosine phosphorylation of most EGFR mutants better than the wild-type receptor. However, gefitinib had quite variable growth-suppressive effects on different EGFR mutant-expressing cells. All tested EGFR mutants have high basal phosphorylation at multiple tyrosine residues. Upon EGF stimulation, the mutated EGFRs did not have apparently stronger phosphorylation at tyrosines 845, 992, 1068, and 1173 than the wild-type receptor. However, stronger phosphorylation at tyrosine 1045 was observed in the S768I, L861Q, E709G, and G719S mutants. The E746-A750 deletion mutant was less responsive to EGF than the wild-type and other mutant receptors. The S768I, L861Q, E709G, and G719S mutants were refractory to EGF-induced ubiquitination and had more sustained tyrosine phosphorylation. E709G and G719S also lacked EGF-induced receptor downregulation. Our results indicate that, in addition to sensitivity to gefitinib, EGFR mutations also caused various changes in EGFR's regulatory mechanisms, which may contribute to the constitutive activation of EGFR mutants and oncogenesis in NSCLC.

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Accession codes

Accessions

GenBank/EMBL/DDBJ

Abbreviations

EGF:

epidermal growth factor

EGFR:

EGF receptor

FCS:

fetal calf serum

HA:

hemagglutinin

IC50:

concentration of 50% inhibition

NSCLC:

non-small-cell lung cancer

TGF-α:

transforming growth factor-α

Tyr:

tyrosine

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Acknowledgements

We are grateful to AstraZeneca for providing gefitinib, to Drs M-C Hung and L-M Wang for the generous gift and helpful discussion, to Dr K-D Lee for technical assistance to this research, to Dr H-M Shih for valuable suggestions, to Ms L-M Huang and Ms C-W Kang for secretarial help. This work was supported by grants from National Health Research Institutes (MG-093-PP-08 and MG-093-PP-07 to SF Huang and Y-R Chen, respectively), Department of Health (DOH94-TD-G-111-016 to Y-R Chen), and National Science Council, Taiwan (NHRI92A1-NSCCA16-5 to S-F Tsai).

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Authors and Affiliations

  1. Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan

    Y-R Chen, C-H Lin, S-T Yang, S-F Hu, Y-T Chen, S-F Tsai & S-F Huang

  2. Institute of Genetics and Genome Research Center, National Yang-Ming University, Taipei, Taiwan

    Y-N Fu & S-F Tsai

  3. Department of Pathology, Chang Gung Memorial Hospital, Taipei, Taiwan

    S-F Huang

  4. Department of Pathology, Municipal Wan-Fang Hospital, Taipei, Taiwan

    S-F Huang

  5. Department of Pathology, School of Medicine, Taipei Medical University, Taipei, Taiwan

    S-F Huang

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  1. Y-R Chen
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Correspondence to S-F Huang.

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Supplementary Information accompanies the paper on Oncogene website (http://www.nature.com/onc)

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Chen, YR., Fu, YN., Lin, CH. et al. Distinctive activation patterns in constitutively active and gefitinib-sensitive EGFR mutants. Oncogene 25, 1205–1215 (2006). https://doi.org/10.1038/sj.onc.1209159

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