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EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer

Oncogene volume 26, pages 1567–1576 (2007)Cite this article

Abstract

Several somatic mutations within the tyrosine kinase domain of epidermal growth factor receptor (EGFR) have been identified that predict clinical response of non-small-cell lung carcinoma (NSCLC) patients to gefitinib. To test the hypothesis that these mutations cause constitutive EGF receptor signaling, and to investigate its mechanistic basis, we expressed representative examples in a null background and analysed their biochemical properties. Each mutation caused significant EGF-independent tyrosine phosphorylation of EGFR, and allowed the receptor to promote Ba/F3 cell mitogenesis in the absence of EGF, arguing that these are oncogenic mutations. Active mutated receptors are present at the cell surface and are fully competent to bind EGF. Recent structural studies show that the inactive EGFR tyrosine kinase domain is autoinhibited by intramolecular interactions between its activation loop and αC helix. We find that mutations predicted to disrupt this autoinhibitory interaction (including several that have not been described in NSCLC) elevate EGF-independent tyrosine kinase activity, thus providing new insight into how somatic mutations activate EGFR and other ErbB family members.

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Acknowledgements

We thank Kate Ferguson and members of the Lemmon laboratory for valuable discussions and comments on the paper. This work was supported by NIH grant R01-CA096768 to MAL.

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  1. S H Choi and J M Mendrola: These authors contributed equally to this work.

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  1. Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA, USA

    S H Choi, J M Mendrola & M A Lemmon

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  1. S H Choi
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Correspondence to M A Lemmon.

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Choi, S., Mendrola, J. & Lemmon, M. EGF-independent activation of cell-surface EGF receptors harboring mutations found in gefitinib-sensitive lung cancer. Oncogene 26, 1567–1576 (2007). https://doi.org/10.1038/sj.onc.1209957

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