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Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade

Oncogene volume 32, pages 2873–2881 (2013)Cite this article

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Abstract

Monoclonal antibodies against the epidermal growth factor receptor (EGFR) are effective cancer therapeutics, but tumors harboring RAS mutations are resistant. To functionally dissect RAS-mediated resistance, we have studied clinically approved anti-EGFR antibodies, cetuximab and panitumumab, in cancer models. Both antibodies were equally cytotoxic in vitro. However, cetuximab, which also triggers antibody-dependent cellular cytotoxicity (ADCC), was more effective than panitumumab in vivo. Oncogenic RAS neutralized the activity of both antibodies in vivo. Mechanistically, RAS upregulated BCL-XL in cancer cell lines and in primary colorectal cancers. Suppression of BCL-XL by short hairpin RNA or treatment with a BH3 mimetic overcame RAS-mediated antibody resistance. In conclusion, RAS-mutant tumors escape anti-EGFR antibody-mediated receptor blockade as well as ADCC in vivo. Pharmacological targeting of RAS effectors can restore sensitivity to antibody therapy.

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Acknowledgements

We thank Sandra Hoffarth, Sarah-Luise Stergar, Kirsten Bruderek, Jeannette Markowetz, Anna Even, Miriam Backs, Ali Sak, Sabine Harde and the staff of the Central Animal Facility, and the Pathology and Molecular Pathology Laboratories, University Hospital Essen, for their support. Robert Coffey, Roman Thomas, Hyatt Balke-Want, Scott W Lowe, Gary P Nolan and Abbott are acknowledged for providing reagents. This work was funded by grants from the Wilhelm Sander-Stiftung (2005.136.3, MS), the Deutsche Forschungsgemeinschaft (SCHU 1541/5-1, MS), Mercator Research Center Ruhr-MERCUR (An-2011-0031, SK) a CESAR Research Fellowship (SK), the Wiedenfeld-Stiftung (SK) and the IFORES program of the Medical Faculty of the University Duisburg-Essen (MS).

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Authors and Affiliations

  1. Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    S Kasper, F Breitenbuecher, J Köhler, T Trarbach & M Schuler

  2. Department of Pathology and Neuropathology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    H Reis, K Worm & K W Schmid

  3. Department of Otorhinolaryngology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    S Brandau

  4. Department of General, Visceral and Transplant Surgery, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany

    A Paul

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  1. S Kasper
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Correspondence to M Schuler.

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Competing interests

Martin Schuler has served as consultant to Amgen; Tanja Trarbach has received research funding, consulting and speaker honoraria from Merck Serono and Amgen. The other authors declare no conflict of interest.

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Kasper, S., Breitenbuecher, F., Reis, H. et al. Oncogenic RAS simultaneously protects against anti-EGFR antibody-dependent cellular cytotoxicity and EGFR signaling blockade. Oncogene 32, 2873–2881 (2013). https://doi.org/10.1038/onc.2012.302

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  • DOI: https://doi.org/10.1038/onc.2012.302

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