The overexpression of ERCC-1 is involved in the resistance of lung cancer cells to cetuximab combined with DDP.
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.
Li
Jing-Jing
JJ
State Key Laboratory of Oncology in South China, Sun Yat-sen University, Guangzhou, China.
Ding
Ya
Y
Li
Dan-Dan
DD
Peng
Rui-Qing
RQ
Feng
Gong-Kan
GK
Zeng
Yi-Xin
YX
Zhu
Xiao-Feng
XF
Zhang
Xiao-Shi
XS
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D002945:Cisplatin / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004357:Drug Synergism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; C071447:ERCC1 protein, human; D004720:Endonucleases; D000068818:Cetuximab; D002945:Cisplatin