State Key Laboratory of Oncogenes & Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
Neoplasia. 2012 Jun;14(6):509-18. doi: 10.1593/neo.12328.
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.
多激酶抑制剂索拉非尼是第一个对人肝细胞癌（HCC）显示活性的口服药物。尽管索拉非尼的临床应用在研究人群中表现出良好的耐受性，但它也会引起多种人类剂量限制毒性。因此，强烈需要降低索拉非尼的总体剂量。我们已经报道，表皮生长因子受体变体 III（EGFRvIII）的表达可以降低 HCC 细胞对化疗药物的敏感性。因此，我们试图探讨 EGFRvIII 是否会影响 HCC 细胞对索拉非尼的敏感性。在这项研究中，我们观察到 EGFRvIII 表达显着降低了 HCC 细胞对索拉非尼的敏感性。为了增强抗肿瘤作用并降低索拉非尼的总体剂量，我们评估了针对 EGFRvIII 的单克隆抗体 CH12 与索拉非尼联合应用对体外和体内表达 EGFRvIII 的 HCC 细胞生长的影响。结果表明，当 CH12 与索拉非尼联合使用时，肿瘤生长抑制作用明显增强，并且抑制生长所需的索拉非尼浓度大大降低。从机制上讲，与单独使用索拉非尼相比，联合用药可以更明显地下调组成性激活细胞外信号调节激酶（ERK）、Akt（Thr308）和信号转导和转录激活因子 3（STAT3）的磷酸化。总的来说，这些发现表明，CH12 与索拉非尼具有相加作用，通过增强索拉非尼对 MEK/ERK、磷酸肌醇 3-激酶/AKT 和 STAT3 通路的抑制作用，强烈抑制表达 EGFRvIII 的 HCC 异种移植物的肿瘤生长。
