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Necroptotic virotherapy of oncolytic alphavirus M1 cooperated with Doxorubicin displays promising therapeutic efficacy in TNBC

Oncogene volume 40, pages 4783–4795 (2021)Cite this article

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Abstract

Triple-negative breast cancer (TNBC) is the most aggressive molecular subtype among breast tumors and remains a challenge even for the most current therapeutic regimes. Here, we demonstrate that oncolytic alphavirus M1 effectively kills both TNBC and non-TNBC. ER-stress and apoptosis pathways are responsible for the cell death in non-TNBC as reported in other cancer types, yet the cell death in TNBC does not depend on these pathways. Transcriptomic analysis reveals that the M1 virus activates necroptosis in TNBC, which can be pharmacologically blocked by necroptosis inhibitors. By screening a library of clinically available compounds commonly used for breast cancer treatment, we find that Doxorubicin enhances the oncolytic effect of the M1 virus by up to 100-fold specifically in TNBC in vitro, and significantly stalls the tumor growth of TNBC in vivo, through promoting intratumoral virus replication and further triggering apoptosis in addition to necroptosis. These findings reveal a novel antitumor mechanism and a new combination regimen of the M1 oncolytic virus in TNBC, and highlight a need to bridge molecular diagnosis with virotherapy.

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Fig. 1: Oncolytic effect of M1 on TNBC and non-TNBC cells in vitro and in vivo.
Fig. 2: M1 triggers ER stress-mediated apoptosis in non-TNBC cells but not in TNBC cells.
Fig. 3: M1 triggers necroptosis-mediated death in TNBC cells.
Fig. 4: Combinatorial drug screen identifies Doxorubicin as the top sensitizer for M1 virus in TNBC cells.
Fig. 5: Doxorubicin inhibits the M1 virus-induced IFN signal by activating the GAS6/AXL pathway.
Fig. 6: Doxorubicin amplifies virus replication of M1, thus leading to necroptosis and apoptosis.
Fig. 7: Combinatorial Doxorubicin and M1 treatment is more effective than M1 alone in vivo.
Fig. 8: Graphical model of differential cell death induced by M1 virus in two breast cancer types and the synergic effect of Doxorubicin andM1 in TNBC.

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Acknowledgements

We thank all authors who contributed to this work. This work was supported by the National Natural Science Foundation of China (No. 81872886), Fundamental Research Funds for the Central Universities (19ykpy36 and 19ykpy166), Guangdong Basic and Applied Basic Research Foundation (2020A1515011446), Pioneering talents project of Guangzhou Development Zone, Guangdong Province (CY2018-012), and Leading Team for Entrepreneurship in Guangzhou, Guangdong Province (201809020004).

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  1. These authors contributed equally: Jiayu Zhang and Ying Liu.

Authors and Affiliations

  1. Department of Pharmacology, Department of Microbiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China

    Jiayu Zhang, Jingyi Tan, Yanming Zhang, Chun-Wa Wong, Xincheng Liu, Lebin Liang, Deli Song, Jia Dan, Yuwei Zhou, Jing Cai, Yuan Lin, Jiankai Liang, Jun Hu, Guangmei Yan & Wenbo Zhu

  2. Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, 600# Tianhe Road, Guangzhou, 510630, China

    Ying Liu

  3. Guangzhou Virotech Pharmaceutical Co., Ltd, #3 Lanyue Road, Science Park, Guangzhou, 510663, China

    Ziqing Lin, Max Sander & Xiaozhi Yang

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Zhang, J., Liu, Y., Tan, J. et al. Necroptotic virotherapy of oncolytic alphavirus M1 cooperated with Doxorubicin displays promising therapeutic efficacy in TNBC. Oncogene 40, 4783–4795 (2021). https://doi.org/10.1038/s41388-021-01869-4

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