The State Key Lab of Pharmaceutical Biotechnology, College of Life Sciences, Nanjing University, Nanjing, China.
Faculty of Pharmacy, Bengbu Medical College, Bengbu, Anhui, China.
J Cell Biochem. 2019 Jan;120(1):756-767. doi: 10.1002/jcb.27434. Epub 2018 Aug 26.
AZD9291, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is highly selective against EGFR T790M-mutant non-small cell lung cancer (NSCLC). On investigating the growth inhibitory effects of AZD9291 on NSCLC and the underlying mechanism, we found that AZD9291 can trigger autophagy-mediated cell death in both A549 and H1975 cells by increasing the expression of phosphatidylethanolamine-modified microtubule-associated protein light-chain 3 (LC3) and decreasing the expression of p62. In the presence of the autophagy inhibitor chloroquine, the AZD9291-induced increase in LC3 level was further augmented. AZD9291 decreased the levels of phosphoinositide-3 kinase (PI3K), protein kinase B (Akt), and phosphorylated Akt. AZD9291-induced cell death was enhanced by Akt knockdown, and the levels of both EGFR and phosphorylated EGFR were decreased by AZD9291. AZD9291 was also found to significantly suppress the tumor growth in H1975 xenograft nude mice. Thus, AZD9291 was found to induce autophagy, decrease in EGFR levels, and show a strong inhibitory effect on NSCLC both in vitro and in vivo. Furthermore, the PI3K/Akt signaling pathway was found to play a critical role in AZD9291-induced cell death.
AZD9291 是一种第三代表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），对 EGFR T790M 突变型非小细胞肺癌（NSCLC）具有高度选择性。在研究 AZD9291 对 NSCLC 的生长抑制作用及其潜在机制时，我们发现 AZD9291 可以通过增加磷脂酰乙醇胺修饰的微管相关蛋白轻链 3（LC3）的表达和降低 p62 的表达，在 A549 和 H1975 细胞中触发自噬介导的细胞死亡。在自噬抑制剂氯喹存在的情况下，AZD9291 诱导的 LC3 水平增加进一步增强。AZD9291 降低了磷酸肌醇 3-激酶（PI3K）、蛋白激酶 B（Akt）和磷酸化 Akt 的水平。Akt 敲低增强了 AZD9291 诱导的细胞死亡，而 AZD9291 降低了 EGFR 和磷酸化 EGFR 的水平。还发现 AZD9291 显著抑制 H1975 异种移植裸鼠的肿瘤生长。因此，AZD9291 被发现能够诱导自噬、降低 EGFR 水平，并在体外和体内对 NSCLC 表现出强烈的抑制作用。此外，还发现 PI3K/Akt 信号通路在 AZD9291 诱导的细胞死亡中发挥关键作用。
