ST3GAL4调控c-Met糖基化修饰介导奥希替尼获得性耐药的作用及机制

三代EGFR-TKI奥希替尼（OSI）疗效显著，但仍面临耐药难题。研究发现c-Met扩增可异常激活下游信号通路导致OSI耐药，但目前c-Met扩增的调控机制尚不清楚。我们前期对OSI耐药细胞RNAseq差异基因筛查发现，唾液酸转移酶ST3GAL4在OSI耐药细胞中突变并异常高表达，且与OSI耐药程度呈正相关。近来研究报道，ST3GAL4表达增高可致c-Met激活。我们的研究亦证实干扰ST3GAL4会使c-Met表达降低。因此，我们推测ST3GAL4可能通过影响c-Met扩增介导OSI耐药，其机制可能是ST3GAL4影响c-Met蛋白的翻译后N-糖基化修饰，调控c-Met蛋白的成熟和过表达，进而介导OSI耐药。本项目通过体内外实验深入研究ST3GAL4调控c-Met过表达介导OSI耐药的作用及其关键机制，以期寻找克服OSI耐药的临床新策略，具有重要科学意义及临床应用价值。

The three generations of EGFR-TKI osimertinib(OSI) has significant efficacy, but it still faces the problem of drug resistance. It has been found that c-Met amplification can abnormally activate downstream signaling pathways leading to OSI resistance, but the regulatory mechanism of c-Met amplification is still unclear. Previous screening of RNAseq in OSI-resistant cell lines showed that sialic acid transferase ST3GAL4 mutated and expressed abnormally high in OSI-resistant cells, and it was positively correlated with the degree of OSI resistance. Recent studies have reported that increased expression of ST3GAL4 can induce c-Met activation. Our study also confirms that interfering with ST3GAL4 reduces c-Met expression. Therefore, we speculate that ST3GAL4 may mediate OSI resistance by influencing c-Met amplification. The mechanism may be that ST3GAL4 affects the post-translational N-glycosylation modification of c-Met protein, regulates the maturation and overexpression of c-Met protein, and then mediates OSI resistance. So, this project aims to investigate the role of ST3GAL4 in regulating c-Met overexpression in OSI resistance through in vivo and in vitro experiments. Its key mechanism, in order to find new clinical strategies to overcome OSI resistance, which has important scientific significance and clinical application value.