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Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer

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A Corrigendum to this article was published on 07 September 2012

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Abstract

Antibodies against epidermal growth factor receptor (EGFR)—cetuximab and panitumumab—are widely used to treat colorectal cancer. Unfortunately, patients eventually develop resistance to these agents. We describe an acquired EGFR ectodomain mutation (S492R) that prevents cetuximab binding and confers resistance to cetuximab. Cells with this mutation, however, retain binding to and are growth inhibited by panitumumab. Two of ten subjects studied here with disease progression after cetuximab treatment acquired this mutation. A subject with cetuximab resistance harboring the S492R mutation responded to treatment with panitumumab.

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Figure 1: Cetuximab-resistant cells are sensitive to the EGFR tyrosine kinase inhibitor gefitinib and the monoclonal antibody to EGFR panitumumab.
Figure 2: Cetuximab-resistant cells harbor a missense mutation (S492R) within the extracellular domain of EGFR.

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Change history

  • 06 July 2012

     In the version of this article initially published, due to an oversight by the authors, the first and last names of one the authors, Somasekar Seshagiri, were incorrectly transposed. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by Instituto de Salud Carlos III (ISCIII) -Subdirección General de Evaluación y Fomento de la Investigación (PS09/01491, PI08/0211 and PI09/1285) and Plan Nacional (PN) de Investigación Científica, Desarrollo e Innovación Tecnológica (I+D+I), iniciativa Ingenio 2010, programa Consolider and ISCIII/FEDER (RD06/0020/0109); PN de I+D+I 2008-20011 and DIUE Generalitat de Catalunya (2009 SGR 321) grants. We thank the Fundació Privada Cellex (Barcelona) for a generous donation to the Medical Oncology Service, Hospital del Mar. We thank the Tumor Bank of Pathology of Hospital del Mar (MARBiobanc), which is supported by FEDER (RD09/0076/00036), and Xarxa de Bancs de Tumors de Catalunya, which is sponsored by PDO (XBTC). We thank L. Roth and R. Cook for assistance with the EGFR binding studies, J. Guillory and J. Stinson for DNA sequencing, and J. Yélamos for key discussions.

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Author notes

  1. Clara Montagut, Alba Dalmases, Jeff Settleman, Francesc Bosch and Joan Albanell: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medical Oncology, Hospital del Mar, Barcelona, Spain

    Clara Montagut, Alba Dalmases, Manuel Gallen, Joaquim Bellmunt, Ana Rovira & Joan Albanell

  2. Cancer Research Program, Institut Municipal d'Investigació Médica (IMIM, Hospital del Mar Research Institute), Barcelona, Spain

    Clara Montagut, Alba Dalmases, Beatriz Bellosillo, Silvia Pairet, Manuel Gallen, Sergi Serrano, Joaquim Bellmunt, Ana Rovira & Joan Albanell

  3. Department of Pathology, Hospital del Mar, Barcelona, Spain

    Beatriz Bellosillo, Silvia Pairet, Mar Iglesias, Marta Salido & Sergi Serrano

  4. Department of Hematology, Vall d'Hebron University Hospital, Barcelona, Spain

    Marta Crespo & Francesc Bosch

  5. Departament de Medicina, Universitat Autonoma de Barcelona, Bellaterra, Spain

    Mar Iglesias, Sergi Serrano & Joan Albanell

  6. Discovery Oncology, Genentech, Inc, San Francisco, California, USA

    Scot Marsters, Siao Ping Tsai, Somasekar Seshagiri & Jeff Settleman

  7. Center for Genomic Regulation, Barcelona, Spain

    André Minoche & Heinz Himmelbauer

  8. Medical School, Universitat Pompeu Fabra (UPF), Barcelona, Spain

    Joaquim Bellmunt

Authors
  1. Clara Montagut
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  2. Alba Dalmases
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  7. Marta Salido
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  8. Manuel Gallen
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  12. Somasekar Seshagiri
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  16. Ana Rovira
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  17. Jeff Settleman
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  18. Francesc Bosch
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  19. Joan Albanell
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Contributions

C.M. designed the overall project. C.M., A.D., A.R., J.S., F.B. and J.A. designed experiments and analyzed data. A.D. performed cell-line and molecular experiments. B.B. and S.P. performed sequencing. M.C. prepared mutant proteins. M.S. performed the fluorescence in situ hybridization analysis. H.H. and A.M. performed the deep sequencing. S.M., S.P.T. and S. Seshagiri carried out the sequencing experiments and recombinant protein assays. M.I. collected and evaluated the tumor samples. S. Serrano supervised the tumor assays. C.M., M.G. and J.B. collected clinical information on the subjects. C.M., J.S., F.B. and J.A. wrote the manuscript.

Corresponding authors

Correspondence to Clara Montagut or Joan Albanell.

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Competing interests

The authors declare no competing financial interests.

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Supplementary Text and Figures

Supplementary Figures 1–6, Supplementary Tables 1 and 2 and Supplementary Methods (PDF 533 kb)

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Montagut, C., Dalmases, A., Bellosillo, B. et al. Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med 18, 221–223 (2012). https://doi.org/10.1038/nm.2609

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  • DOI: https://doi.org/10.1038/nm.2609

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