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  3. Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors

Non-small cell lung cancers (NSCLCs) oncolysis using coxsackievirus B5 and synergistic DNA-damage response inhibitors

  • Signal Transduct Target Ther. 2023 Sep 25;8(1):366. doi: 10.1038/s41392-023-01603-4.
Bopei Cui # 1 2,  Lifang Song # 1 2,  Qian Wang # 1,  Kelei Li 1 3,  Qian He 1,  Xing Wu 1,  Fan Gao 1,  Mingchen Liu 1,  Chaoqiang An 1 3,  Qiushuang Gao 1,  Chaoying Hu 1,  Xiaotian Hao 1,  Fangyu Dong 1 4,  Jiuyue Zhou 4,  Dong Liu 1 5,  Ziyang Song 1 6,  Xujia Yan 1 5,  Jialu Zhang 1,  Yu Bai 1,  Qunying Mao 7,  Xiaoming Yang 8 9,  Zhenglun Liang 10
Affiliations

Affiliations

  • 1 Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China.
  • 2 National Engineering Technology Research Center for Combined Vaccines, Wuhan, China.
  • 3 Beijing Minhai Biotechnology Co., Ltd, Beijing, China.
  • 4 Taibang Biologic Group, Beijing, China.
  • 5 Changchun Institute of Biological Products Co., Ltd, Changchun, China.
  • 6 Shanghai Institute of Biological Products Co., Ltd, Shanghai, China.
  • 7 Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China. maoqunying@126.com.
  • 8 National Engineering Technology Research Center for Combined Vaccines, Wuhan, China. yangxiaoming@sinopharm.com.
  • 9 China National Biotec Group Company Limited, Beijing, China. yangxiaoming@sinopharm.com.
  • 10 Division of Hepatitis and Enterovirus Vaccines, NHC Key Laboratory of Research on Quality and Standardization of Biotech Products, NMPA Key Laboratory for Quality Research and Evaluation of Biological Products, Institute of Biological Products, National Institutes for Food and Drug Control, Beijing, China. lzhenglun@126.com.
  • # Contributed equally.
PMID: 37743418 DOI: 10.1038/s41392-023-01603-4
Abstract

With the continuous in-depth study of the interaction mechanism between viruses and hosts, the virus has become a promising tool in Cancer treatment. In fact, many oncolytic viruses with selectivity and effectiveness have been used in Cancer therapy. Human Enterovirus is one of the most convenient sources to generate oncolytic viruses, however, the high seroprevalence of some enteroviruses limits its application which urges to exploit more oncolytic enteroviruses. In this study, coxsackievirus B5/Faulkner (CV-B5/F) was screened for its potential oncolytic effect against non-small cell lung cancers (NSCLCs) through inducing Apoptosis and Autophagy. For refractory NSCLCs, DNA-dependent protein kinase (DNA-PK) or ataxia telangiectasia mutated protein (ATM) inhibitors can synergize with CV-B5/F to promote refractory cell death. Here, we showed that viral Infection triggered endoplasmic reticulum (ER) stress-related pro-apoptosis and Autophagy signals, whereas repair for double-stranded DNA breaks (DSBs) contributed to cell survival which can be antagonized by inhibitor-induced cell death, manifesting exacerbated DSBs, Apoptosis, and Autophagy. Mechanistically, PERK pathway was activated by the combination of CV-B5/F and inhibitor, and the irreversible ER stress-induced exacerbated cell death. Furthermore, the degradation of activated STING by ERphagy promoted viral replication. Meanwhile, no treatment-related deaths due to CV-B5/F and/or inhibitors occurred. Conclusively, our study identifies an oncolytic CV-B5/F and the synergistic effects of inhibitors of DNA-PK or ATM, which is a potential therapy for NSCLCs.

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