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Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members

Oncogene volume 27, pages 3944–3956 (2008)Cite this article

Abstract

The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10–20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to cetuximab. Cells developing acquired resistance to cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, cetuximab-resistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to cetuximab.

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Abbreviations

DMSO:

dimethyl sulfoxide

EGFR:

epidermal growth factor receptor

ELISA:

enzyme-linked immunosorbent assay

HGF:

hepatocyte growth factor

mAb:

monoclonal antibody

MAPK:

mitogen-activated protein kinase

NSCLC:

nonsmall cell lung cancer

PI(3)K:

phosphatidylinositol 3′-kinase

RTK:

receptor tyrosine kinase

SCC:

squamous cell carcinoma

TKD:

tyrosine kinase domain

TKI:

tyrosine kinase inhibitor

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Acknowledgements

We thank AstraZeneca (gefitinib), Genentech (erlotinib, 2C4), ImClone (cetuximab), OSI (erlotinib) and Pfizer Global Research (PHA665752 and CI-1033) for supplying EGFR- and cMET-targeting agents. This work was supported in part by NIH R01 CA 113448-01 (PMH) and American Cancer Society Postdoctoral Fellowship (DLW).

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Author notes

  1. D L Wheeler and S Huang: These authors contributed equally to this work.

  2. P M Harari: This author holds research and/or consulting agreements with Amgen, AstraZeneca, Genentech and ImClone.

Authors and Affiliations

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

    D L Wheeler, S Huang, T J Kruser, M M Nechrebecki, E A Armstrong, S Benavente, V Gondi, K-T Hsu & P M Harari

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  1. D L Wheeler
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  2. S Huang
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  3. T J Kruser
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  7. V Gondi
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  9. P M Harari
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Correspondence to P M Harari.

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Wheeler, D., Huang, S., Kruser, T. et al. Mechanisms of acquired resistance to cetuximab: role of HER (ErbB) family members. Oncogene 27, 3944–3956 (2008). https://doi.org/10.1038/onc.2008.19

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