Huang Dianshuai, Fan Qingjie, Liu Zhiyi, Zhang Shuqin, Huang Wei, Li Hongrui, Liang Chongyang, Sun Fei
Institute of Frontier Medical Science, Jilin University, Changchun 130021, Jilin, China.
Department of Biopharmacy, School of Pharmaceutical Sciences, Jilin University, Changchun 130021, Jilin, China.
Cancers (Basel). 2020 Feb 16;12(2):456. doi: 10.3390/cancers12020456.
The precise role of Epidermal Growth Factor Receptor (EGFR) in Hepatocellular carcinoma (HCC) cells is unknown and EGFR inhibitors have not achieved positive clinical results. The rapid and drastic internalization of EGFR has been proved to successfully treat EGFR inhibitor-resistant patients in recent clinical trials. Here, the anti-tumor efficacy of a protein (rLZ-8) from was evaluated, it was demonstrated that rLZ-8 could bind to EGFR specifically, drastically enter into Hepatoma cells, abrogate endosomal recycling and induce HCC cell death. Surprisingly, we screened a monoclonal antibody which possesses competitive binding site with rLZ-8, it also trigger catastrophic EGFR internalization. This result suggests that it is necessary to investigate the interface of EGFR and rLZ-8 complex. An internalization related epitope (S222/K269) was identified on the dimerization arm of EGFR extracellular domain (ECD). These results suggest vulnerability of HCC cells to catastrophic EGFR internalization that can be targeted by a novel epitope and point to the possible exploitation in the design of anti-EGFR therapeutic biologics for HCC therapy.
表皮生长因子受体（EGFR）在肝癌（HCC）细胞中的精确作用尚不清楚，且EGFR抑制剂尚未取得积极的临床效果。最近的临床试验证明，EGFR的快速和剧烈内化已成功治疗EGFR抑制剂耐药患者。在此，评估了一种来自[具体来源未提及]的蛋白质（rLZ-8）的抗肿瘤功效，结果表明rLZ-8可特异性结合EGFR，大量进入肝癌细胞，消除内体循环并诱导肝癌细胞死亡。令人惊讶的是，我们筛选出一种与rLZ-8具有竞争性结合位点的单克隆抗体，它也能引发灾难性的EGFR内化。这一结果表明有必要研究EGFR与rLZ-8复合物的界面。在EGFR细胞外结构域（ECD）的二聚化臂上鉴定出一个与内化相关的表位（S222/K269）。这些结果表明肝癌细胞易受灾难性EGFR内化的影响，这种内化可被一个新的表位靶向，并指出在设计用于肝癌治疗的抗EGFR治疗性生物制剂方面可能的应用。
