Identification and characterization of alphavirus M1 as a selective oncolytic virus targeting ZAP-defective human cancers

Yuan Lin, Haipeng Zhang, Jiankai Liang, Kai Li, Wenbo Zhu, Liwu Fu, Fang Wang, Xiaoke Zheng, Huijuan Shi, Sihan Wu, Xiao Xiao, Lijun Chen, Lipeng Tang, Min Yan, Xiaoxiao Yang, Yaqian Tan, Pengxin Qiu, Yijun Huang, Wei Yin, Xinwen SuHaiyan Hu, Jun Hu, Guangmei Yan

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

Abstract

Oncolytic virotherapy is a growing treatment modality that uses replicating viruses as selective antineoplastic agents. Safety and efficacy considerations dictate that an ideal oncolytic agent would discriminate between normal and cancer cells on the basis of common genetic abnormalities in human cancers. Here, we identify a naturally occurring alphavirus (M1) as a novel selective killer targeting zinc-finger antiviral protein (ZAP)-deficient cancer cells. In vitro, in vivo, and ex vivo studies showed potent oncolytic efficacy and high tumor tropism of M1. We showed that the selectivity depends on ZAP deficiency by systematic identification. A large-scale multicenter pathology study using tissue microarrays reveals that ZAP is commonly deficient in human cancers, suggesting extensive application prospects for M1. Additionally, M1 killed cancer cells by inducing endoplasmic reticulum stress-mediated apoptosis. Our report provides novel insights into potentially personalized cancer therapy using oncolytic viruses.

Original languageEnglish (US)
Pages (from-to)E4504-E4512
JournalProceedings of the National Academy of Sciences of the United States of America
Volume111
Issue number42
DOIs
StatePublished - Oct 21 2014
Externally publishedYes

Keywords

  • Personalized medicine
  • Translational inhibition
  • Unfolded protein response

ASJC Scopus subject areas

  • General

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