BRAF-and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress

Victoria Roulstone, Malin Pedersen, Joan Kyula, David Mansfield, Aadil A. Khan, Grainne Mcentee, Michelle Wilkinson, Eleni Karapanagiotou, Matt Coffey, Richard Marais, Adel Jebar, Fiona Errington-Mais, Alan Melcher, Richard Vile, Hardev Pandha, Martin Mclaughlin, Kevin J. Harrington

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

Reovirus type 3 (Dearing) (RT3D) infection is selective for cells harboring a mutated/activated RAS pathway. Therefore, in a panel of melanoma cell lines (including RAS mutant, BRAF mutant and RAS/BRAF wild-type), we assessed therapeutic combinations that enhance/suppress ERK1/2 signaling through use of BRAF/MEK inhibitors. In RAS mutant cells, the combination of RT3D with the BRAF inhibitor PLX4720 (paradoxically increasing ERK1/2 signaling in this context) did not enhance reoviral cytotoxicity. Instead, and somewhat surprisingly, RT3D and BRAF inhibition led to enhanced cell kill in BRAF mutated cell lines. Likewise, ERK1/2 inhibition, using the MEK inhibitor PD184352, in combination with RT3D resulted in enhanced cell kill in the entire panel. Interestingly, TCID 50 assays showed that BRAF and MEK inhibitors did not affect viral replication. Instead, enhanced efficacy was mediated through ER stress-induced apoptosis, induced by the combination of ERK1/2 inhibition and reovirus infection. In vivo, combined treatments of RT3D and PLX4720 showed significantly increased activity in BRAF mutant tumors in both immune-deficient and immune-competent models. These data provide a strong rationale for clinical translation of strategies in which RT3D is combined with BRAF inhibitors (in BRAF mutant melanoma) and/or MEK inhibitors (in BRAF and RAS mutant melanoma).

Original languageEnglish (US)
Pages (from-to)931-942
Number of pages12
JournalMolecular Therapy
Volume23
Issue number5
DOIs
StatePublished - May 9 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

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    Roulstone, V., Pedersen, M., Kyula, J., Mansfield, D., Khan, A. A., Mcentee, G., Wilkinson, M., Karapanagiotou, E., Coffey, M., Marais, R., Jebar, A., Errington-Mais, F., Melcher, A., Vile, R., Pandha, H., Mclaughlin, M., & Harrington, K. J. (2015). BRAF-and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress. Molecular Therapy, 23(5), 931-942. https://doi.org/10.1038/mt.2015.15