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Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling

Oncogene volume 33, pages 1700–1712 (2014)Cite this article

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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 V600DBRAF/V600EBRAF 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 V600DBRAF/V600EBRAF 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/EBRAF mutant tumors.

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Acknowledgements

We would like to thank Dr Khin Thway and Dr Michelle Wilkinson for their assistance with data acquisition and analysis. This work was supported in part by research grants from the Myfanwy Townsend Melanoma Research Fund and the Cotswold Trust.

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Authors and Affiliations

  1. Divisions of Cancer Biology, Targeted Therapy Team, The Institute of Cancer Research, London, UK

    J N Kyula, A A Khan, D Mansfield, E M Karapanagiotou, M McLaughlin, V Roulstone, S Zaidi, T Pencavel, Y Touchefeu, R Seth & K J Harrington

  2. Genelux Corp, San Diego Science Center, San Diego, CA, USA

    N G Chen, Y A Yu, Q Zhang & A A Szalay

  3. Leeds Institute of Molecular Medicine, Leeds, UK

    A A Melcher & R G Vile

  4. Molecular Medicine Program, Mayo Clinic, Rochester, MN, USA

    R G Vile

  5. Postgraduate Medical School, The University of Surrey, Guildford, UK

    H S Pandha & M Ajaz

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Correspondence to J N Kyula.

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Competing interests

Aladar Szalay is president and a shareholder of GeneLux corporation. Kevin Harrington receives funding from GeneLux corporation in support of laboratory research. The remaining authors declare no conflict of interest.

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Kyula, J., Khan, A., Mansfield, D. et al. Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling. Oncogene 33, 1700–1712 (2014). https://doi.org/10.1038/onc.2013.112

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