The overexpression of ERCC-1 is involved in the resistance of lung cancer cells to cetuximab combined with DDP

Abstract

Cetuximab, an antibody against epidermal growth factor receptor, has been approved for the

treatment of colorectal carcinoma and head and neck squamous cell carcinoma. There is

increasing evidence that cetuximab can reverse the resistance to irinotecan (CPT-11) and

oxaliplatin. Since cisplatin (DDP) is a widely used chemotherapeutics this study examined

whether cetuximab could reverse the resistance to DDP.  Combined treatment with DDP and

cetuximab resulted in an increase in the cytotoxicity of DDP in a DDP-sensitive lung cancer

cell line (A549), but not in a DDP-resistant derivative (A549/DDP). Meantime, DDP

activated the EGFR pathway in A549 cells but not in A549/DDP cells in a ligand-independent

fashion. After the expression of excision repair cross-complementation group 1 (ERCC-1)

protein was inhibited by small interfering RNA (siRNA), the potential of cetuximab to

enhance DDP-mediated cytotoxicity was restored in A549/DDP cells. These data suggested

that ERCC-1 was involved in the resistance of cetuximab combined with DDP as

overexpression of ERCC-1 prohibits the activation of EGFR pathway, which would facilitate

the preselection of lung cancer patients for the treatment of cetuximab combined with DDP.