title: Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in (V600D/E)BRAF mutant melanoma depends on JNK and TNF-α signaling.
abstract: Melanoma is an aggressive skin cancer that carries an extremely poor prognosis when local invasion, nodal spread or systemic metastasis has occurred. Recent advances in melanoma biology have revealed that RAS-RAF-MEK-ERK signaling has a pivotal role in governing disease progression and treatment resistance. Proof-of-concept clinical studies have shown that direct BRAF inhibition yields impressive responses in advanced disease but these are short-lived as treatment resistance rapidly emerges. Therefore, there is a pressing need to develop new targeted strategies for BRAF mutant melanoma. As such, oncolytic viruses represent a promising cancer-specific approach with significant activity in melanoma. This study investigated interactions between genetically-modified vaccinia virus (GLV-1h68) and radiotherapy in melanoma cell lines with BRAF mutant, Ras mutant or wild-type genotype. Preclinical studies revealed that GLV-1h68 combined with radiotherapy significantly increased cytotoxicity and apoptosis relative to either single agent in (V600D)BRAF/(V600E)BRAF mutant melanoma in vitro and in vivo. The mechanism of enhanced cytotoxicity with GLV-1h68/radiation (RT) was independent of viral replication and due to attenuation of JNK, p38 and ERK MAPK phosphorylation specifically in BRAF mutant cells. Further studies showed that JNK pathway inhibition sensitized BRAF mutant cells to GLV-1h68-mediated cell death, mimicking the effect of RT. GLV-1h68 infection activated MAPK signaling in (V600D)BRAF/(V600E)BRAF mutant cell lines and this was associated with TNF-α secretion which, in turn, provided a prosurvival signal. Combination GLV-1h68/RT (or GLV-1h68/JNK inhibition) caused abrogation of TNF-α secretion. These data provide a strong rationale for combining GLV-1h68 with irradiation in (V600D/E)BRAF mutant tumors.
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: J N
authors.initials: JN
authors.lastname: Kyula
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Khan
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: D
authors.initials: D
authors.lastname: Mansfield
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Karapanagiotou
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: M
authors.initials: M
authors.lastname: McLaughlin
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: V
authors.initials: V
authors.lastname: Roulstone
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: S
authors.initials: S
authors.lastname: Zaidi
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: T
authors.initials: T
authors.lastname: Pencavel
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: Y
authors.initials: Y
authors.lastname: Touchefeu
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: R
authors.initials: R
authors.lastname: Seth
authors.affiliation: Genelux Corp, San Diego Science Center, San Diego, CA, USA.
authors.forename: N G
authors.initials: NG
authors.lastname: Chen
authors.affiliation: Genelux Corp, San Diego Science Center, San Diego, CA, USA.
authors.forename: Y A
authors.initials: YA
authors.lastname: Yu
authors.affiliation: Genelux Corp, San Diego Science Center, San Diego, CA, USA.
authors.forename: Q
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Leeds Institute of Molecular Medicine, Leeds, UK.
authors.forename: A A
authors.initials: AA
authors.lastname: Melcher
authors.affiliation: 1] Leeds Institute of Molecular Medicine, Leeds, UK [2] Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA.
authors.forename: R G
authors.initials: RG
authors.lastname: Vile
authors.affiliation: Postgraduate Medical School, The University of Surrey, Guildford, UK.
authors.forename: H S
authors.initials: HS
authors.lastname: Pandha
authors.affiliation: Postgraduate Medical School, The University of Surrey, Guildford, UK.
authors.forename: M
authors.initials: M
authors.lastname: Ajaz
authors.affiliation: Genelux Corp, San Diego Science Center, San Diego, CA, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Szalay
authors.affiliation: Targeted Therapy Team, Divisions of Cancer Biology, The Institute of Cancer Research, London, UK.
authors.forename: K J
authors.initials: KJ
authors.lastname: Harrington
mesh_terms: D000818:Animals; D016923:Cell Death; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008545:Melanoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D050130:Oncolytic Virotherapy / Q000379:methods*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D011897:Random Allocation; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*; D014616:Vaccinia virus / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D014409:Tumor Necrosis Factor-alpha; D048493:Proto-Oncogene Proteins B-raf; D048031:JNK Mitogen-Activated Protein Kinases