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

J. N. Kyula, A. A. Khan, D. Mansfield, E. M. Karapanagiotou, M. Mclaughlin, V. Roulstone, S. Zaidi, T. Pencavel, Y. Touchefeu, R. Seth, N. G. Chen, Y. A. Yu, Q. Zhang, A. A. Melcher, Richard Geoffrey Vile, H. S. Pandha, M. Ajaz, A. A. Szalay, K. J. Harrington

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 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 inV600D/E BRAF mutant tumors.

Original languageEnglish (US)
Pages (from-to)1700-1712
Number of pages13
JournalOncogene
Volume33
Issue number13
DOIs
StatePublished - Mar 27 2014

Fingerprint

Vaccinia
Melanoma
Radiation
Radiotherapy
Oncolytic Viruses
Cell Line
MAP Kinase Signaling System
Vaccinia virus
Mitogen-Activated Protein Kinase Kinases
Radiation Effects
Skin Neoplasms
p38 Mitogen-Activated Protein Kinases
Disease Progression
Neoplasms
Cell Death
Genotype
Phosphorylation
Apoptosis
Neoplasm Metastasis
Therapeutics

Keywords

  • Apoptosis
  • GLV-1h68
  • JNK
  • Oncolytic vaccinia
  • RT
  • TNF-α

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Kyula, J. N., Khan, A. A., Mansfield, D., Karapanagiotou, E. M., Mclaughlin, M., Roulstone, V., ... Harrington, K. J. (2014). Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling. Oncogene, 33(13), 1700-1712. https://doi.org/10.1038/onc.2013.112

Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling. / Kyula, J. N.; Khan, A. A.; Mansfield, D.; Karapanagiotou, E. M.; Mclaughlin, M.; Roulstone, V.; Zaidi, S.; Pencavel, T.; Touchefeu, Y.; Seth, R.; Chen, N. G.; Yu, Y. A.; Zhang, Q.; Melcher, A. A.; Vile, Richard Geoffrey; Pandha, H. S.; Ajaz, M.; Szalay, A. A.; Harrington, K. J.

In: Oncogene, Vol. 33, No. 13, 27.03.2014, p. 1700-1712.

Research output: Contribution to journalArticle

Kyula, JN, Khan, AA, Mansfield, D, Karapanagiotou, EM, Mclaughlin, M, Roulstone, V, Zaidi, S, Pencavel, T, Touchefeu, Y, Seth, R, Chen, NG, Yu, YA, Zhang, Q, Melcher, AA, Vile, RG, Pandha, HS, Ajaz, M, Szalay, AA & Harrington, KJ 2014, 'Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling', Oncogene, vol. 33, no. 13, pp. 1700-1712. https://doi.org/10.1038/onc.2013.112
Kyula, J. N. ; Khan, A. A. ; Mansfield, D. ; Karapanagiotou, E. M. ; Mclaughlin, M. ; Roulstone, V. ; Zaidi, S. ; Pencavel, T. ; Touchefeu, Y. ; Seth, R. ; Chen, N. G. ; Yu, Y. A. ; Zhang, Q. ; Melcher, A. A. ; Vile, Richard Geoffrey ; Pandha, H. S. ; Ajaz, M. ; Szalay, A. A. ; Harrington, K. J. / Synergistic cytotoxicity of radiation and oncolytic Lister strain vaccinia in V600D/EBRAF mutant melanoma depends on JNK and TNF-α signaling. In: Oncogene. 2014 ; Vol. 33, No. 13. pp. 1700-1712.
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