title: Cetuximab induces eme1-mediated DNA repair: a novel mechanism for cetuximab resistance.
abstract: 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.
authors.affiliation: Institute of Neuropathology, Medical Faculty, RWTH Aachen University and JARA-BRAIN (Jülich Aachen Research Alliance Brain) Translational Medicine, Aachen, Germany; Department of Neurosurgery, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany. Electronic address: adreier@ukaachen.de.
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Weinandy
authors.affiliation: Department of Radiation Oncology, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany.
authors.forename: Marc D
authors.initials: MD
authors.lastname: Piroth
authors.affiliation: Institute of Neuropathology, Medical Faculty, RWTH Aachen University and JARA-BRAIN (Jülich Aachen Research Alliance Brain) Translational Medicine, Aachen, Germany.
authors.forename: Anand
authors.initials: A
authors.lastname: Goswami
authors.affiliation: Institute of Neuropathology, Medical Faculty, RWTH Aachen University and JARA-BRAIN (Jülich Aachen Research Alliance Brain) Translational Medicine, Aachen, Germany.
authors.forename: Kay
authors.initials: K
authors.lastname: Nolte
authors.affiliation: Institute of Neuropathology, Medical Faculty, RWTH Aachen University and JARA-BRAIN (Jülich Aachen Research Alliance Brain) Translational Medicine, Aachen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Sellhaus
authors.affiliation: Institute of Neuropathology, Medical Faculty, RWTH Aachen University and JARA-BRAIN (Jülich Aachen Research Alliance Brain) Translational Medicine, Aachen, Germany.
authors.forename: Jose
authors.initials: J
authors.lastname: Gerardo-Nava
authors.affiliation: Department of Radiation Oncology, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Eble
authors.affiliation: Department of Tissue Engineering and Textile Implants, Applied Medical Engineering-Helmholtz Institute for Biomedical Engineering, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Weinandy
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Cornelissen
authors.affiliation: Department of Neurosurgery, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Clusmann
authors.affiliation: Institute of Biochemistry and Molecular Biology, Medical Faculty, RWTH Aachen University and JARA-BRAIN Translational Medicine, Aachen, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Lüscher
authors.affiliation: Institute of Neuropathology, Medical Faculty, RWTH Aachen University and JARA-BRAIN (Jülich Aachen Research Alliance Brain) Translational Medicine, Aachen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Weis
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology; D001932:Brain Neoplasms / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D000068818:Cetuximab; D004247:DNA / Q000096:biosynthesis; D004260:DNA Repair / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm; D004706:Endodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy / Q000473:pathology / Q000532:radiotherapy; D006801:Humans; D055550:Protein Stability; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004247:DNA; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; C507947:Eme1 protein, human; D004706:Endodeoxyribonucleases; D000068818:Cetuximab
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