title: Role of MAPK in oncolytic herpes viral therapy in triple-negative breast cancer.
abstract: 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.
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gholami
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: C-H
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Gao
authors.affiliation: Department of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.
authors.forename: E
authors.initials: E
authors.lastname: Lou
authors.affiliation: Molecular Cytology Core Facility, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: S
authors.initials: S
authors.lastname: Fujisawa
authors.affiliation: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Carson
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: J E
authors.initials: JE
authors.lastname: Nnoli
authors.affiliation: Molecular Pharmacology and Chemistry Program, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: T-C
authors.initials: TC
authors.lastname: Chou
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bromberg
authors.affiliation: 1] Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA [2] Department of Surgery, City of Hope Medical Center, Duarte, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Fong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D045744:Cell Line, Tumor; D015536:Down-Regulation; D004789:Enzyme Activation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000502:physiology*; D011897:Random Allocation; D015398:Signal Transduction; D064726:Triple Negative Breast Neoplasms / Q000201:enzymology / Q000473:pathology / Q000628:therapy* / Q000821:virology*; D014779:Virus Replication; D023041:Xenograft Model Antitumor Assays
chemical_list: D020928:Mitogen-Activated Protein Kinases