Gholami S, Chen C-H, Gao S, Lou E, Fujisawa S, Carson J, Nnoli J E, Chou T-C, Bromberg J, Fong Y
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Cancer Gene Ther. 2014 Jul;21(7):283-9. doi: 10.1038/cgt.2014.28. Epub 2014 Jun 13.
Triple-negative breast cancers (TNBCs) have poor clinical outcomes owing to a lack of targeted therapies. Activation of the MEK/MAPK pathway in TNBC has been associated with resistance to conventional chemotherapy and biologic agents and has a significant role in poor clinical outcomes. NV1066, a replication-competent herpes virus, infected, replicated in and killed all TNBC cell lines (MDA-MB-231, HCC1806, HCC38, HCC1937, HCC1143) tested. Greater than 90% cell kill was achieved in more-sensitive lines (MDA-MB-231, HCC1806, HCC38) by day 6 at a multiplicity of infection (MOI) of 0.1. In less-sensitive lines (HCC1937, HCC1143), NV1066 still achieved >70% cell kill by day 7 (MOI 1.0). In vivo, mean volume of flank tumors 14 days after treatment with NV1066 was 57 versus 438 mm(3) in controls (P=0.002). NV1066 significantly downregulated p-MAPK activation by 48 h in all cell lines in vitro and in MDA-MB-231 xenografts in vivo. NV1066 demonstrated synergistic effects with a MEK inhibitor, PD98059 in vitro. We demonstrate that oncolytic viral therapy (NV1066) effectively treats TNBC with correlation to decreased MEK/MAPK signaling. These findings merit future studies investigating the potential role of NV1066 as a sensitizing agent for conventional chemotherapeutic and biologic agents by downregulating the MAPK signaling pathway.
三阴性乳腺癌（TNBC）由于缺乏靶向治疗，临床预后较差。TNBC中MEK/MAPK通路的激活与对传统化疗和生物制剂的耐药性相关，并且在不良临床预后中起重要作用。NV1066是一种具有复制能力的疱疹病毒，它能感染、在所有测试的TNBC细胞系（MDA-MB-231、HCC1806、HCC38、HCC1937、HCC1143）中复制并杀死这些细胞。在感染复数（MOI）为0.1时，到第6天，更敏感的细胞系（MDA-MB-231、HCC1806、HCC38）的细胞杀伤率超过90%。在不太敏感的细胞系（HCC1937、HCC1143）中，到第7天，NV1066（MOI为1.0）的细胞杀伤率仍达到＞70%。在体内，用NV1066治疗14天后，侧腹肿瘤的平均体积在对照组中为438mm³，而在治疗组中为57mm³（P = 0.002）。在体外所有细胞系以及体内MDA-MB-231异种移植瘤中，NV1066在48小时内显著下调p-MAPK的激活。在体外，NV1066与MEK抑制剂PD98059表现出协同作用。我们证明溶瘤病毒疗法（NV1066）能有效治疗TNBC，且与MEK/MAPK信号传导的降低相关。这些发现值得未来开展研究，以探究NV1066通过下调MAPK信号通路作为传统化疗和生物制剂增敏剂的潜在作用。
