NDRG1抑制表皮生长因子受体酪氨酸激酶信号通路增强结直肠癌对西妥昔单抗敏感性的分子机制研究

The metastatic colorectal cancer (mCRC), has gradually become one of the hotspots in clinical treatment. It has been proven that patients with unresectable mCRC will benefit from the treatment of targeted therapy. Moreover, there are several RCT trials indicated that tumor location and mutation status of RAS/BRAF/PIK3CA gene can significantly affect the sensitivity of the anti-epidermal growth factor receptor (EGFR) antibody, cetuximab (Cet), in mCRC treatment, which has been accepted by different official Guidelines. The deeper analysis of the data from these trials, however, we noticed that KRAS wild-type CRC patients are not fully sensitive to Cet treatment, and there are still Cet sensitive cases in patients within KRAS mutation population. Therefore, it is necessary to further identify more precise biomarkers evaluating Cet sensitivity to improve the therapeutic effect of individualized comprehensive treatment of mCRC. Based on our previous study, we demonstrated that the tumor suppressor NDRG1, which has been systemically investigated by our research team for years, may enhance the Cet sensitivity to CRC cells in vitro, that may be induced by affecting the epidermal growth factor receptor tyrosine kinase signaling pathway (RTKs). Above all, we speculate that NDRG1 may enhance the Cet sensitivity by (1) regulating the expression, distribution, phosphorylation, and dimerization of EGFR; (2) regulating the process of endocytosis and degradation of EGFR; (3) inhibiting the abnormal activation of RTKs signaling pathway, such as EGFR-downstream RAS, PI3K, PKCs, and STATs signaling pathways. This study aims at exploring and demonstrating the underlying mechanisms of Cet sensitivity regulated by NDRG1, providing a theoretical basis for finding new targets and new evaluation biomarkers of individualized treatment for mCRC.

转移性结直肠癌(mCRC)的治疗逐渐成为临床热点。靶向药物可使无法行根治性切除的mCRC患者获益。研究表明肿瘤部位及RAS/BRAF/PIK3CA基因突变情况可判断mCRC患者对于抗表皮生长因子受体(EGFR)抗体西妥昔单抗(Cet)的敏感性，并被指南收录。然而深入挖掘这些研究数据后我们发现：KRAS wt患者并不全对Cet敏感，KRAS mut患者中仍存在Cet敏感病例。因此，发现能更精准评估Cet敏感性的新指标，有可能使mCRC个体化综合治疗疗效得到进一步提高。本课题组前期发现NDRG1可能促进CRC细胞对Cet敏感性，结合预实验我们推测：NDRG1可能通过调控EGFR表达/分布、磷酸化及二聚体化、调控EGFR内吞与降解、以及抑制其下游受体酪氨酸激酶信号通路的异常激活，进而增强CRC对Cet敏感性。本研究旨在为mCRC的治疗寻找新靶标及个体化治疗疗效的新评价指标提供理论依据。

转移性结直肠癌(mCRC)的治疗逐渐成为临床热点。靶向药物可使无法行根治性切除的mCRC患者获益。研究表明肿瘤部位及RAS/BRAF/PIK3CA基因突变情况可判断mCRC患者对于抗表皮生长因子受体(EGFR)抗体西妥昔单抗(Cet)的敏感性，并被指南收录。然而深入挖掘这些研究数据后我们发现：KRAS wt患者并不全对Cet敏感，KRAS mut患者中仍存在Cet敏感病例。因此，发现能更精准评估Cet敏感性的新指标，有可能使mCRC个体化综合治疗疗效得到进一步提高。本研究首次报道了NDRG1可能促进CRC细胞对Cet敏感性。通过进一步深入研究，我们发现：NDRG1可能通过调控EGFR表达/分布、磷酸化及二聚体化、调控EGFR内吞与降解、以及抑制其下游受体酪氨酸激酶信号通路的异常激活，进而增强CRC对Cet敏感性。本研究旨在为mCRC的治疗寻找新靶标及个体化治疗疗效的新评价指标提供理论依据。