Roulstone, V, Pedersen, M, Kyula, J et al. (14 more authors) (2015) BRAF- and MEK-targeted small molecule inhibitors exert enhanced antimelanoma effects in combination with oncolytic reovirus through ER stress. Molecular Therapy, 23 (5). pp. 931-942. ISSN 1525-0016
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).
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © The American Society of Gene & Cell Therapy. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND 4.0). |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cancer and Pathology (LICAP) > Oncology and Cancer Research - Labs (Leeds) |
Depositing User: | Symplectic Publications |
Date Deposited: | 26 Aug 2015 11:02 |
Last Modified: | 14 Apr 2017 04:19 |
Published Version: | http://dx.doi.org/10.1038/mt.2015.15 |
Status: | Published |
Publisher: | Nature Publishing Group |
Identification Number: | 10.1038/mt.2015.15 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:87350 |