Introduction: Crizotinib is a kinase inhibitor targeting c-MET/ALK/ROS1 used as the first-line chemical for the treatment of non-small cell lung cancer (NSCLC) with ALK mutations. Although c-MET is frequently overexpressed in 35-72% of NSCLC, most NSCLCs are primarily resistant to crizotinib treatment./nMethod: A set of NSCLC cell lines were used to test the effect of chidamide on the primary crizotinib resistance in vitro and in vivo. Relationships between the synergistic effect of chidamide and c-MET expression and RNA methylation were systemically studied with a battery of molecular biological assays./nResults: We found for the first time that chidamide could sensitize the effect of crizotinib in a set of ALK mutation-free NSCLC cell lines, especially those with high levels of c-MET expression. Notably, chidamide could not increase the sensitivity of NSCLC cells to crizotinib cultured in serum-free medium without hepatocyte growth factor (HGF; a c-MET ligand). In contrast, the addition of HGF into the serum-/HGF-free medium could restore the synergistic effect of chidamide. Moreover, the synergistic effect of chidamide could also be abolished either by treatment with c-MET antibody or siRNA-knockdown of c-MET expression. While cells with low or no c-MET expression were primarily resistant to chidamide-crizotinib cotreatment, enforced c-MET overexpression could increase the sensitivity of these cells to chidamide-crizotinib cotreatment. Furthermore, chidamide could decrease c-MET expression by inhibiting mRNA N6-methyladenosine (m6A) modification through the downregulation of METTL3 and WTAP expression. Chidamide-crizotinib cotreatment significantly suppressed the activity of c-MET downstream molecules./nConclusion: Chidamide downregulated c-MET expression by decreasing its mRNA m6A methylation, subsequently increasing the crizotinib sensitivity of NSCLC cells in a c-MET-/HGF-dependent manner.

中文翻译：

---

Chidamide 通过降低 c-MET mRNA 甲基化增加非小细胞肺癌对克唑替尼的敏感性。

简介：克唑替尼是一种靶向 c-MET/ALK/ROS1 的激酶抑制剂，用作治疗具有ALK突变的非小细胞肺癌 (NSCLC) 的一线化学品。虽然C-MET是在NSCLC的35-72％经常过度，非小细胞肺癌最主要耐克里唑替尼treatment./n方法： NSCLC细胞系的一组被用来测试西达对主克里唑替尼抗性的效果的体外和体内。使用一系列分子生物学分析系统地研究了西达本胺和 c-MET 表达的协同作用与 RNA 甲基化之间的关系。/n结果：我们首次发现西达本胺可以使克唑替尼在一组无ALK突变的 NSCLC 细胞系中的作用敏感，尤其是那些具有高水平 c- MET表达的细胞系。值得注意的是，西达本胺不能增加 NSCLC 细胞对在不含肝细胞生长因子（HGF；一种 c-MET 配体）的无血清培养基中培养的克唑替尼的敏感性。相反，将 HGF 添加到无血清/HGF 的培养基中可以恢复西达本胺的协同作用。此外，西达本胺的协同作用也可以通过用 c-MET 抗体处理或 siRNA 敲低 c- MET表达来消除。虽然具有低或无 c- MET表达的细胞主要对西达本胺-克唑替尼共治疗具有抗性，但强制 c-MET过表达可以增加这些细胞对西达本胺-克唑替尼联合治疗的敏感性。此外，西达本胺可以通过下调METTL3和WTAP表达来抑制 mRNA N6-甲基腺苷 (m6A) 修饰，从而降低 c- MET表达。Chidamide-crizotinib 联合治疗显着抑制 c-MET 下游分子的活性。/n结论： Chidamide通过降低其 mRNA m6A 甲基化来下调 c- MET表达，随后增加 c-MET-/HGF 依赖型 NSCLC 细胞对克唑替尼的敏感性方式。