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The Monoclonal Antibody CH 12 Enhances the Sorafenib-Mediated Growth Inhibition of Hepatocellular Carcinoma Xenografts Expressing Epidermal Growth Factor Receptor Variant III 1
| Content Provider | Semantic Scholar |
|---|---|
| Author | Yang, Yaqiong Jiang, Hua Gao, Huiping Kong, Juan Zhang, Pengwei Hu, Suwen Shi, Bizhi Zhang, Pengfei Yao, Ming Li, Zonghai |
| Copyright Year | 2014 |
| Abstract | The multikinase inhibitor sorafenib is the first oral agent to show activity against human hepatocellular carcinoma (HCC). Although the clinical application of sorafenib has shown good tolerability in the studied populations, it also causes multiple human dose-limiting toxicities. Thus, there is a strong need to reduce the overall dose of sorafenib. We have reported that the epidermal growth factor receptor variant III (EGFRvIII) expression can decrease the sensitivity of HCC cells to chemotherapeutic drugs. Therefore, we sought to explore whether EGFRvIII can affect the sensitivity of HCC cells to sorafenib. In this study, we observed that EGFRvIII expression significantly decreased the sensitivity of HCC cells to sorafenib. To enhance the antitumor effect and reduce the overall dose of sorafenib, we evaluated the combined effects of CH12, a monoclonal antibody against EGFRvIII, and sorafenib on the growth of HCC cells expressing EGFRvIII in vitro and in vivo. The results showed that, when CH12 was combined with sorafenib, the tumor growth suppression effect was significantly increased, and the concentration of sorafenib required for growth inhibition was substantially reduced. Mechanistically, the combination could more noticeably downregulate the phosphorylation of constitutively active extracellular signal–regulated kinase (ERK), Akt (Thr308), and signal transducer and activator of transcription 3 (STAT3) than sorafenib alone. Collectively, these findings demonstrate that CH12 interacts additively with sorafenib to strongly inhibit the tumor growth of HCC xenografts expressing EGFRvIII by enhancing the sorafenib-mediated inhibition of the MEK/ERK, phosphoinositide 3-kinase/AKT, and STAT3 pathways. Neoplasia (2012) 14, 509–518 Introduction Hepatocellular carcinoma (HCC) is the fifth most common cancer and the third leading cause of cancer-related death worldwide [1,2]. Over the past decades, the incidence of HCC has increased worldwide, especially in eastern Asia and sub-Saharan Africa [1,3]. HCC is clinically characterized by its invasiveness, poor prognosis, and limited therapeutic opportunities. At present, surgery is the most effective treatment for HCC. However, tumor recurrence after a curative liver resection is high [4]. For advanced stage disease, systemic pharmacotherapy is usually the final and main treatment. Previous clinical investigations have shown that traditional systemic chemotherapy cannot provide survival benefits for patients with HCC [2]. Thus, there is a Abbreviations: EGFR, epidermal growth factor receptor; EGFRvIII, epidermal growth factor receptor variant III; ERK, extracellular signal–regulated kinase; HCC, hepatocellular carcinoma; STAT3, signal transducer and activator of transcription 3 Address all correspondence to: Dr Zonghai Li, No. 25/Ln2200, XieTu Rd, Shanghai 200032, China. E-mail: zonghaili@shsmu.edu.cn This study is supported by the “Twelfth Five-year Plan” for Science & Technology Research of China (grant no. 2012ZX10002015-007), the National Natural Science Foundation (grant no. 30901820), the Key Program Project of the Shanghai Science and Technology Committee (grant no. 10431903700), and the research fund of the State Key Laboratory of Oncogenes and Related Genes (grant no. 91-10-06). These authors contributed equally to this work. Received 9 February 2012; Revised 2 May 2012; Accepted 4 May 2012 Copyright © 2012 Neoplasia Press, Inc. All rights reserved 1522-8002/12/$25.00 DOI 10.1593/neo.12328 www.neoplasia.com Volume 14 Number 6 June 2012 pp. 509–518 509 |
| File Format | PDF HTM / HTML |
| Alternate Webpage(s) | https://core.ac.uk/download/pdf/82673222.pdf |
| Language | English |
| Access Restriction | Open |
| Content Type | Text |
| Resource Type | Article |
