Cetuximab Induces Eme1-Mediated DNA Repair: a Novel Mechanism for Cetuximab Resistance12

• Published in: Neoplasia (New York, N.Y.) N.Y.), 2014-04, Vol.16 (3), p.207-220.e4
• Main Authors: Weinandy, Agnieszka, Piroth, Marc D., Goswami, Anand, Nolte, Kay, Sellhaus, Bernd, Gerardo-Nava, Jose, Eble, Michael, Weinandy, Stefan, Cornelissen, Christian, Clusmann, Hans, Lüscher, Bernhard, Weis, Joachim
• Format: Article
• Language: English
• ISSN: 1522-8002; 1476-5586
• DOI: 10.1016/j.neo.2014.03.004

Overexpression of the epidermal growth factor receptor (EGFR) is observed in a large number of neoplasms. The monoclonal antibody cetuximab/Erbitux is frequently applied to treat EGFR-expressing tumors. However, the application of cetuximab alone or in combination with radio- and/or chemotherapy often yields only little benefit for patients. In the present study, we describe a mechanism that explains resistance of both tumor cell lines and cultured primary human glioma cells to cetuximab. Treatment of these cells with cetuximab promoted DNA synthesis in the absence of increased proliferation, suggesting that DNA repair pathways were activated. Indeed, we observed that cetuximab promoted the activation of the DNA damage response pathway and prevented the degradation of essential meiotic endonuclease 1 homolog 1 (Eme1), a heterodimeric endonuclease involved in DNA repair. The increased levels of Eme1 were necessary for enhanced DNA repair, and the knockdown of Eme1 was sufficient to prevent efficient DNA repair in response to ultraviolet-C light or megavoltage irradiation. These treatments reduced the survival of tumor cells, an effect that was reversed by cetuximab application. Again, this protection was dependent on Eme1. Taken together, these results suggest that cetuximab initiates pathways that result in the stabilization of Eme1, thereby resulting in enhanced DNA repair. Accordingly, cetuximab enhances DNA repair, reducing the effectiveness of DNA-damaging therapies. This aspect should be considered when using cetuximab as an antitumor agent and suggests that Eme1 is a negative predictive marker.