2. Academic Validation
  3. ZX-29, a novel ALK inhibitor, induces apoptosis via ER stress in ALK rearrangement NSCLC cells and overcomes cell resistance caused by an ALK mutation

ZX-29, a novel ALK inhibitor, induces apoptosis via ER stress in ALK rearrangement NSCLC cells and overcomes cell resistance caused by an ALK mutation

  • Biochim Biophys Acta Mol Cell Res. 2020 Jul;1867(7):118712. doi: 10.1016/j.bbamcr.2020.118712.
Wenfeng Gou 1,  Zengqiang Li 2,  Xiaobo Xu 2,  Jiwei Shen 2,  Ming Guo 3,  Xuejiao Zhou 2,  Xiaoning Zhang 2,  Yingliang Wu 2,  Xin Zhai 4,  Daiying Zuo 5
Affiliations

Affiliations

  • 1 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China; Tianjin Key Laboratory of Radiation Medicine and Molecular Nuclear Medicine, Institute of Radiation Medicine, Peking Union Medical College & Chinese Academy of Medical Sciences, 238 Baidi Road, Nankai District, Tianjin 300192, China.
  • 2 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 3 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China.
  • 4 Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zhaixin_syphu@126.com.
  • 5 Department of Pharmacology, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenhe District, Shenyang 110016, China. Electronic address: zuodaiying@163.com.
PMID: 32224191 DOI: 10.1016/j.bbamcr.2020.118712
Abstract

Although anaplastic lymphoma kinase (ALK) inhibitors have good clinical efficacy, the inevitable development of drug resistance is the most common obstacle to their clinical application. There is an urgent need to develop more effective and selective ALK inhibitors to overcome the problem of drug resistance. Here, we screened a series of ALK inhibitors and found that ZX-29 displayed potent cytotoxic activity against ALK rearrangement non-small cell lung Cancer (NSCLC) NCI-H2228 cells. Then, we investigated the antitumor effects of ZX-29. We demonstrated that ZX-29 time- and dose-dependently inhibited the viability of NCI-H2228 cells, induced cell cycle arrest in the G1 phase, and then they subsequently progressed into cell death. The type of cell death induced by ZX-29 was Apoptosis through endoplasmic reticulum (ER) stress. Interestingly, ZX-29 induced protective Autophagy, and inhibiting Autophagy could enhance the antitumor effect of ZX-29. Furthermore, ZX-29 suppressed tumor growth in a mouse xenograft model. More importantly, ZX-29 could overcome the drug resistance caused by the ALK G1202R mutation. In conclusion, we demonstrated that ZX-29 showed excellent anti-ALK rearrangement NSCLC activity in vitro and in vivo and overcame the drug resistance caused by an ALK mutation. Therefore, ZX-29 is a promising antitumor drug targeting ALK rearrangement or ALK G1202R mutation NSCLC.

Keywords

ALK; Apoptosis; Drug resistance; ER stress; NSCLC.

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