Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer
Endogenous Akt Activity Promotes Virus Entry and Predicts Efficacy of Novel Chimeric Orthopoxvirus in Triple-Negative Breast Cancer
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DOI：
10.1016/j.omto.2018.04.001
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发表时间：
2018-06-29
影响因子：
5.7
通讯作者：
Chen, Nanhai G.
中科院分区：
文献类型：
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作者：
Choi, Audrey H.;O'Leary, Michael P.;Chen, Nanhai G.
三阴性乳腺癌（TNBC）是一种复发率高、预后差的侵袭性乳腺癌亚型。在这里，我们描述了一种新的嵌合正痘病毒（CF 33），其有效地杀死TNBC。在四种TNBC细胞系中体外测定细胞毒性。通过标准空斑试验检查病毒复制。在无胸腺裸鼠中产生两种原位TNBC异种移植物模型，并瘤内注射CF 33。CF 33在体外是有效的，在具有磷脂酰肌醇3-激酶（PI 3 K）/Akt途径突变的TNBC系中观察到有效的细胞毒性和有效的细胞内复制，所述磷脂酰肌醇3-激酶（PI 3 K）/Akt途径突变导致内源性磷酸化Akt（p-Akt）活性（BT549、Hs 578 T和MDA-MB-468）。使用更高的MOI克服了野生型PI 3 K/Akt途径细胞系MDA-MB-231对CF 33的相对抗性。该病毒在体内有效，在两种异种移植模型中肿瘤尺寸显著减小。在机制上，CF 33似乎与牛痘病毒在Akt介导和低pH介导的病毒进入方面具有相似的性质。总之，CF 33在体外和体内表现出有效的抗肿瘤作用，其中通过TNBC细胞系中内源性Akt活性的存在预测最有效的作用。进一步研究其作用机制以及基因修饰以增强其天然病毒嗜性是临床前开发的必要条件。
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with high recurrence rate and poor prognosis. Here, we describe a novel, chimeric orthopoxvirus (CF33) that efficiently kills TNBC. Cytotoxicity was assayed in vitro in four TNBC cell lines. Viral replication was examined through standard plaque assay. Two orthotopic TNBC xenograft models were generated in athymic nude mice and were injected with CF33 intratumorally. CF33 was effective in vitro with potent cytotoxicity and efficient intracellular replication observed in TNBC lines with phosphatidylinositol 3-kinase (PI3K)/Akt pathway mutations that resulted in endogenous phospho-Akt (p-Akt) activity (BT549, Hs578T, and MDA-MB-468). Relative resistance to CF33 by wild-type PI3K/Akt pathway cell line MDA-MB-231 was overcome using higher MOI. The virus was effective in vivo with significant tumor size reduction in both xenograft models. Mechanistically, CF33 appears to share similar properties to vaccinia virus with respect to Akt-mediated and low-pH-mediated viral entry. In summary, CF33 demonstrated potent antitumoral effect in vitro and in vivo, with the most potent effect predicted by the presence of endogenous Akt activity in the TNBC cell line. Further investigation of its mechanism of action as well as genetic modifications to enhance its natural viral tropism are warranted for preclinical development.