title: The monoclonal antibody CH12 augments 5-fluorouracil-induced growth suppression of hepatocellular carcinoma xenografts expressing epidermal growth factor receptor variant III.
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.
authors.affiliation: State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University, School of Medicine, Shanghai, China.
authors.forename: Hua
authors.initials: H
authors.lastname: Jiang
authors.forename: Qiongna
authors.initials: Q
authors.lastname: Dong
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Luo
authors.forename: Bizhi
authors.initials: B
authors.lastname: Shi
authors.forename: Huamao
authors.initials: H
authors.lastname: Wang
authors.forename: Huiping
authors.initials: H
authors.lastname: Gao
authors.forename: Juan
authors.initials: J
authors.lastname: Kong
authors.forename: Jiqin
authors.initials: J
authors.lastname: Zhang
authors.forename: Zonghai
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050744:Dihydrouracil Dehydrogenase (NAD+) / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000276:immunology; D005472:Fluorouracil / Q000008:administration & dosage; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D009962:Orotate Phosphoribosyltransferase / Q000378:metabolism; D034622:RNA Interference; D013940:Thymidylate Synthase / Q000235:genetics / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; C585627:CH12 monoclonal antibody; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C575048:MIRN520 microRNA, human; D035683:MicroRNAs; C410723:epidermal growth factor receptor VIII; D050744:Dihydrouracil Dehydrogenase (NAD+); D013940:Thymidylate Synthase; D009962:Orotate Phosphoribosyltransferase; D066246:ErbB Receptors; D005472:Fluorouracil
keywords: 5-FU; 5-Fluorouracil; 5-fluorouracil; Combination therapy; DPYD; EGFR; EGFRvIII; Epidermal growth factor receptor variant III; HCC; Hepatocellular carcinoma; OPRT; TS; dihydrouracil dehydrogenase; epidermal growth factor receptor; epidermal growth factor receptor variant III; hepatocellular carcinoma; mAb CH12; orotate phosphoribosyltransferase; thymidylate synthase