gms | German Medical Science

Objective: Overexpression of the epidermal growth factor receptor (EGFR) is observed in a large number of neoplasms including high grade gliomas. Diverse strategies have been established to target and inhibit EGFR, including monoclonal antibodies and tyrosine kinase inhibitors. The recombinant antibody Cetuximab (Merck) is frequently applied to treat EGFR-expressing solid tumors. In initial clinical trials cetuximab was used for treatments of high grade gliomas. However the application of cetuximab alone or in combination with radio- and/or chemotherapy still fails in a high percentage of the treated patients. Tumor progression is frequently associated with alterations in DNA repair pathways. This dysfunctional DNA repair capacity results in genomic instability of tumor cells. Recent reports have demonstrated that defective DNA repair in tumor cells can be linked to acquired therapy resistance. In the present study we addressed the mechanism of acquired cetuximab resistance in several tumor entities.

Method: Cetuximab-mediated effects were analyzed in several human tumor cell lines (epidermoid carcinoma cell line A431, glioblastoma cell line A172 and breast cancer cell line MDA-MB-231) as well as in primary cultures of human glioblastoma.

Results: We found that cetuximab led to increased protein levels of the DNA repair-related endonuclease Eme1 in tumor cell lines as well as in primary cultures of human glioblastoma cells. Eme1, a regulatory subunit of the heterodimeric endonuclease Mus81/Eme1 belongs to the XPF/Mus81 protein family. It acts by cleaving stalled or blocked replication forks and thereby promoting DNA repair and maintaining genomic integrity. The elevated Eme1 protein levels led to increased DNA repair in the cetuximab treated cells. Accordingly, cetuximab reduced the effectiveness of DNA damaging therapies such as UVC or megavoltage-irradiation.

Conclusions: Previous clinical studies showed contradictory outcomes when cetuximab is used in combination with radiotherapy. One of the mostly used treatments following surgical resection is postoperative irradiation. We propose that the radiotherapy may fail in combination with cetuximab when this antibody will activate Eme1 mediated DNA repair. These elevated levels of the Mus81/Eme1 will result in increased survival of the tumor cells. Taken together, these findings strongly suggest that Eme1 is a negative predictive marker for a combination therapy of cetuximab with a treatment that induces DNA damage such as radiotherapy.