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EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy

Oncogene volume 27, pages 957–965 (2008)Cite this article

Abstract

Mutations in epidermal growth factor receptor (EGFR) kinase domain associate with clinical responses to EGFR inhibitors and are frequently observed in non-small cell lung cancer (NSCLC) patients in East Asian populations. Clinically identified EGFR mutations cause constitutive receptor activation. The activating mechanisms were unclear but appeared to be different among EGFR mutants. We found that EGFR mutants had different sensitivity to an Src inhibitor PP2. S768I and L861Q mutants were less sensitive to Src suppression than others. Mutation at tyrosine 869 (845) residue, an Src phosphorylation site, decreased the phosphorylation levels of wild-type EGFR and other mutants, but not that of S768I and L861Q mutants, suggesting that S768I and L861Q mutants became Src independent for their activation and biological functions. In contrast, cells expressing EGFR-L858R or exon 19 deletion mutants were more sensitive to PP2 than cells expressing wild-type EGFR. Interestingly, EGFR with exon 19-deletion/T790M double mutations, which was resistant to gefitinib, remained sensitive to PP2. Taken together, our data indicate that Src inhibitors might be effective in treating NSCLC harboring specific types of EGFR mutations.

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Abbreviations

Del:

deletion

EGF:

epidermal growth factor

EGFR:

EGF receptor

NSCLC:

non-small cell lung cancer

pEGFR:

phospho-EGFR

SDS:

sodium dodecyl sulfate

Tyr (Y):

tyrosine

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Acknowledgements

We are grateful to Drs M-C Hung and L-M Wang for providing research materials, 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-095-PP-04) and Department of Health, Taiwan (DOH94-TD-G-111-016) to Y-R Chen.

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Authors and Affiliations

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

    Y-N Fu, C-L Yeh, H H-Y Cheng, C-H Yang, S-F Tsai, S-F Huang & Y-R Chen

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

    S-F Tsai

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

    S-F Huang

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  1. Y-N Fu
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Correspondence to Y-R Chen.

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

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Fu, YN., Yeh, CL., Cheng, HY. et al. EGFR mutants found in non-small cell lung cancer show different levels of sensitivity to suppression of Src: implications in targeting therapy. Oncogene 27, 957–965 (2008). https://doi.org/10.1038/sj.onc.1210684

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