AZD9291 promotes autophagy and inhibits PI3K/Akt pathway in NSCLC cancer cells. Issue 1 (26th August 2018)

• Record Type: Journal Article
• Authors: Zhang, Zhirui; Zhang, Mengxiao; Liu, Hao; Yin, Wu
• Is Part Of: Journal of cellular biochemistry. Volume 120:Issue 1(2019)
• Page Start: 756
• Page End: 767
• Publication Date: 2018-08-26
• Subjects: autophagy -- AZD9291 -- epidermal growth factor receptor (EGFR) -- phosphoinositide‐3 kinase/protein kinase B (PI3K/Akt); Cytochemistry -- Periodicals; 572
• DOI: 10.1002/jcb.27434
• Languages: English
• ISSNs: 0730-2312

Abstract

Abstract: 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. Abstract : 1. AZD9291 induces autophagy in A549 and H1975 non–small cell lung cancer (NSCLC) cell lines. 2. AZD9291 inhibits the PI3K/Akt pathway in NSCLC cancer cells. 3. AZD9291 suppresses H1975 tumor growth in nude mice.