Effects of magnolin and chloroform parts of Flos Magnoliae on gene expression in NCI-H1975 cells,and genetic changes after EGFR TKI resistance

we demonstrated that N-Myc Downstream Regulated 1 (NDRG1) interacts with and restrains Neuregulin 2 (NRG2) to down-regulate the EGFR. This inhibition prevents excessive autophagy protection, thereby reducing EGFR TKI drug resistance in lung cancer cell lines and xenograft mouse models. Activation of NDRG1 using compounds like Chinese herb extract Flos Magnoliae and its active monomer (magnolin) restored sensitivity in resistant cell lines to EGFR TKIs and delayed resistance in lung cancer xenograft mice. These findings highlight a mechanism for resistance to a molecularly targeted therapy and provide a potential therapeutic target for overcoming resistance to EGFR TKIs, including the second-generation inhibitor afatinib To investigate the genetic changes after EGFR TKI resistance and to find the inhibitors of resistance genes

本研究证实，N-Myc下游调控蛋白1（N-Myc Downstream Regulated 1，NDRG1）可与神经调节蛋白2（Neuregulin 2，NRG2）相互作用并对其产生抑制效应，进而下调表皮生长因子受体（EGFR）的表达水平。该抑制作用可阻断过度的细胞自噬保护机制，由此降低肺癌细胞系及异种移植小鼠模型中EGFR-TKI的耐药性。使用中药提取物辛夷（Flos Magnoliae）及其活性单体木兰脂素（magnolin）这类化合物激活NDRG1，可恢复耐药细胞系对EGFR-TKI的敏感性，并延缓肺癌异种移植小鼠的耐药进程。上述研究结果揭示了分子靶向治疗耐药的潜在机制，并为克服包括第二代抑制剂阿法替尼（afatinib）在内的EGFR-TKI耐药问题提供了潜在治疗靶点。本研究旨在探究EGFR-TKI耐药后的遗传改变，并筛选耐药基因的抑制剂。