Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma

Haoyu Deng; Huitao Liu; Tanya de Silva; YuanChao Xue; Yasir Mohamud; Chen Seng Ng; Junyan Qu; Jingchun Zhang; William W G Jia; William W Lockwood; Honglin Luo

doi:10.1016/j.omto.2019.07.003

Coxsackievirus Type B3 Is a Potent Oncolytic Virus against KRAS-Mutant Lung Adenocarcinoma

Mol Ther Oncolytics. 2019 Jul 23:14:266-278. doi: 10.1016/j.omto.2019.07.003. eCollection 2019 Sep 27.

Authors

Haoyu Deng^{1

2

3}, Huitao Liu^{1

2}, Tanya de Silva^{2

4}, YuanChao Xue^{1

2}, Yasir Mohamud^{1

2}, Chen Seng Ng¹, Junyan Qu^{1

2

5}, Jingchun Zhang^{1

2}, William W G Jia⁶, William W Lockwood^{2

4}, Honglin Luo^{1

2}

Affiliations

¹ Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.
² Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
³ Department of Vascular Surgery, RenJi Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China.
⁴ Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
⁵ Centre for Infectious Disease, West China Hospital, Sichuan University, Chengdu, China.
⁶ Department of Surgery, Division of Neurosurgery, University of British Columbia, Vancouver, BC, Canada.

Abstract

KRAS mutant (KRAS ^mut ) lung adenocarcinoma is a refractory cancer without available targeted therapy. The current study explored the possibility to develop coxsackievirus type B3 (CVB3) as an oncolytic agent for the treatment of KRAS ^mut lung adenocarcinoma. In cultured cells, we discovered that CVB3 selectively infects and lyses KRAS ^mut lung adenocarcinoma cells (A549, H2030, and H23), while sparing normal lung epithelial cells (primary, BEAS2B, HPL1D, and 1HAEo) and EGFR ^mut lung adenocarcinoma cells (HCC4006, PC9, H3255, and H1975). Using stable cells expressing a single driver mutation of either KRAS ^G12V or EGFR ^L858R in normal lung epithelial cells (HPL1D), we further showed that CVB3 specifically kills HPL1D-KRAS ^G12V cells with minimal harm to HPL1D-EGFR ^L858R and control cells. Mechanistically, we demonstrated that aberrant activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and compromised type I interferon immune response in KRAS ^mut lung adenocarcinoma cells serve as key factors contributing to the sensitivity to CVB3-induced cytotoxicity. Lastly, we conducted in vivo xenograft studies using two immunocompromised mouse models. Our results revealed that intratumoral injection of CVB3 results in a marked tumor regression of KRAS ^mut lung adenocarcinoma in both non-obese diabetic (NOD) severe combined immunodeficiency (SCID) gamma (NSG) and NOD-SCID xenograft models. Together, our findings suggest that CVB3 is an excellent candidate to be further developed as a targeted therapy for KRAS ^mut lung adenocarcinoma.

Keywords: EGFR mutation; ERK1/2 signaling; KRAS mutation; coxsackievirus B3; enterovirus; lung adenocarcinoma; oncolytic virus; type I interferon; virotherapy.