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, TCID50 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).
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antineoplastic Agents / administration & dosage
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Antineoplastic Agents / pharmacology
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Apoptosis / drug effects
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Apoptosis / genetics
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Benzamides / administration & dosage
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Benzamides / pharmacology
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Caspases / metabolism
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Cell Line, Tumor
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Cell Survival / drug effects
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Cell Survival / genetics
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Disease Models, Animal
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Drug Resistance, Neoplasm
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Endoplasmic Reticulum Stress*
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Enzyme Activation
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Fibroblasts / drug effects
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Fibroblasts / metabolism
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Humans
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Indoles / administration & dosage
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Indoles / pharmacology
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Melanoma / genetics
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Melanoma / metabolism*
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Melanoma / pathology
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Melanoma / therapy
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Mitogen-Activated Protein Kinases / antagonists & inhibitors*
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Mitogen-Activated Protein Kinases / genetics
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Mitogen-Activated Protein Kinases / metabolism
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Mutation
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Oncogene Protein p21(ras) / genetics
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Oncolytic Virotherapy*
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Oncolytic Viruses*
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Protein Kinase Inhibitors / administration & dosage
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Protein Kinase Inhibitors / pharmacology*
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Proto-Oncogene Proteins B-raf / antagonists & inhibitors*
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Reoviridae / physiology*
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Signal Transduction / drug effects
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Sulfonamides / administration & dosage
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Sulfonamides / pharmacology
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Tumor Necrosis Factor-alpha / metabolism
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Xenograft Model Antitumor Assays
Substances
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
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Antineoplastic Agents
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Benzamides
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Indoles
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PLX 4720
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Protein Kinase Inhibitors
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Sulfonamides
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Tumor Necrosis Factor-alpha
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Proto-Oncogene Proteins B-raf
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Mitogen-Activated Protein Kinases
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Caspases
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Oncogene Protein p21(ras)