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  • Original Article
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Nuclear EGFR contributes to acquired resistance to cetuximab

Oncogene volume 28, pages 3801–3813 (2009)Cite this article

Abstract

Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma and metastatic colorectal cancer. Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin, heparin-binding EGF and β-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and resensitization to cetuximab. In addition, expression of a nuclear localization sequence-tagged EGFR in cetuximab-sensitive cells increased resistance to cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with cetuximab-resistant tumors with inhibitors of SFKs in combination with cetuximab.

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Abbreviations

AR:

amphiregulin

cEGFR:

cytoplasmic epidermal growth factor receptor

DMSO:

dimethyl sulfoxide

EGF:

epidermal growth factor

EGFR:

epidermal growth factor receptor

HB-EGF:

heparin-binding epidermal growth factor

HNSCC:

head and neck squamous cell carcinoma

nEGFR:

nuclear epidermal growth factor receptor

NLS:

nuclear localization sequence

NSCLC:

non-small cell lung cancer

PCNA:

proliferating cell nuclear antigen

p-Tyr:

phospho-tyrosine

SCC:

squamous cell carcinoma

SFK:

Src family kinases

TACE:

tumor necrosis factor-α converting enzyme

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Acknowledgements

We thank Shyhmin Huang, Eric A Armstrong and Sergio Benavente for their initial work in the establishment of cetuximab-resistant H226 cell lines. Cetuximab and dasatinib were kindly provided by ImClone and Bristol Myers Squibb, respectively.

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Authors and Affiliations

  1. Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA

    C Li, M Iida, E F Dunn, A J Ghia & D L Wheeler

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  1. C Li
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  2. M Iida
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Correspondence to D L Wheeler.

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Li, C., Iida, M., Dunn, E. et al. Nuclear EGFR contributes to acquired resistance to cetuximab. Oncogene 28, 3801–3813 (2009). https://doi.org/10.1038/onc.2009.234

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