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.

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“…However, we observed that PIC–Nal–IRI transiently downregulates γ-H2AX expression in the first 24 h of incubation. This is presumably due to the activation of Cet-induced DNA repair pathways (e.g., Eme1) as shown by others [47]. Lastly, depolarization of the mitochondrial membrane was observed at 24 h after light activation of PIC–Nal–IRI, PIC-Nal, or PIC, but not with Nal–IRI alone, suggesting cytosolic mitochondrial photodamage is achieved primarily by PIC, as reported by us [9].…”

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“…Weinandy et al ( 89 ) suggested that Eme1 protein is significantly increased under cetuximab resistance, which often means that treatment may fail. Mechanistically, elevated levels of Mus81/Eme1 endonuclease during cetuximab treatment promoted DNA repair and ultimately led to tumor cell growth.…”

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“…The administration of mAb 806 has shown promising results in preclinical glioma models. 36,37 However, data on its putative clinical activity are still lacking. Further strategies include the administration of antibody-drug conjugates (ADCs), which consist of an anti-EGFR antibody conjugated to potent cytotoxic drugs.…”