受体酪氨酸激酶EPHA3调控HER2蛋白稳定性介导HER2阳性乳腺癌细胞曲妥珠单抗治疗耐药的作用及机制研究

HER2蛋白于膜表面的稳定性及有效暴露是曲妥珠单抗与之结合并拮抗肿瘤的根本，但肿瘤进展中存在膜表面HER2蛋白下调，并与预后不良相关。项目前期发现患者肿瘤组织受体酪氨酸激酶EPHA3高表达者有较差的含曲妥珠单抗的新辅助治疗疗效，且曲妥珠单抗治疗耐药者EPHA3亦高表达；也发现其高表达可降低肿瘤细胞和小鼠移植瘤曲妥珠单抗敏感性，同时细胞膜表面HER2水平显著降低；EPHA3活化可诱导HER2蛋白内吞并促进CD44表达。项目聚焦的科学问题是EPHA3影响HER2蛋白膜表面稳定性介导乳腺癌曲妥珠单抗治疗耐药的机制。我们拟以EPHA3为研究切入点，系统解析和明确患者EPHA3表达与曲妥珠单抗耐药的相关性；揭示其通过诱导HER2蛋白内吞及遮蔽物形成的双重作用影响HER2蛋白膜表面稳定性及有效性介导曲妥珠单抗耐药的机制，探索和形成靶向EPHA3逆转曲妥珠单抗耐药的新策略。

The stability and validity of HER2 on the membrane is the basis for trastuzumab to antagonize the tumor. However, the down-regulation of HER2 on the membrane surface exists and is closely related to poor prognosis. In our preliminary study, we found that high expression of EPHA3 associated with lower response rate of trastuzumab based neoadjuvant therapy. And high expression of EPHA3 could reduce trastuzumab sensitivity of tumor cells and xenografts. Activation of EPHA3 could induce the receptor endocytosis of HER2 protein, and at the same time HER2 levels on the cell membrane surface were significantly reduced. It also induces CD44 upregulation and the formation of CD44-hyaluronic acid-HER2 complex, resulting in the dual effect of HER2 protein down-regulation. Therefore, this project focuses on the regulating the stability and validity of HER2 in trastuzumab treatment. We aim to study the effect of EPHA3 on trastuzumab resistance, to reveal its dual effects and molecular mechanism of regulating the stability and validity of HER2 in breast cancer cells, and to explore the interventional strategy, so as to establish a new strategy for targeting EPHA3 to reverse trastuzumab resistance in HER2 positive breast cancer cells.