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Cancer letters

The monoclonal antibody CH12 augments 5-fluorouracil-induced growth suppression of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III.


PMID 24007863

Abstract

5-Fluorouracil (5-FU) is one of the most common chemotherapeutic agents used for the treatment of hepatocellular carcinoma (HCC). However, chemoresistance has precluded the use of 5-FU alone in clinical regimens. Combination therapies with 5-FU and other anticancer agents are considered to be a therapeutic option for patients with HCC. We previously reported that the expression of epidermal growth factor receptor variant III (EGFRvIII) can decrease the sensitivity of HCC cells to 5-FU. To overcome this problem, in this study, we elucidated the mechanism underlying EGFRvIII-mediated 5-FU resistance. We observed that EGFRvIII expression can induce miR-520d-3p downregulation and the ensuing upregulation of the transcription factor E2F-1 and the enzyme thymidylate synthase (TS), which may lead to drug resistance. Intriguingly, we found that CH12, a monoclonal antibody directed against EGFRvIII, and 5-FU together had an additive antitumor effect on EGFRvIII-positive HCC xenografts and significantly improved survival in all mice with established tumors when compared with either 5-FU or CH12 alone. Mechanistically, compared with 5-FU alone, the combination more noticeably downregulated EGFR phosphorylation and Akt phosphorylation as well as the expression of the apoptotic protector Bcl-xL and the cell cycle regulator cyclin D1. Additionally, the combination upregulated the expression of the cell cycle inhibitor p27 in in vivo treatment. More interestingly, CH12 treatment upregulated miR-520-3p and downregulated E2F-1 and TS at the mRNA and protein levels. Collectively, these observations suggest that the combination of 5-FU with mAb CH12 is a potential means of circumventing EGFRvIII-mediated 5-FU resistance in HCC.