Abstract
Inhibition of RAF/MEK/ERK signaling is beneficial for many patients with BRAF(V600E)-mutated melanoma. However, primary and secondary resistances restrict long-lasting therapy success. Combination therapies are therefore urgently needed. Here, we evaluate the cellular effect of combining a MEK inhibitor with a genotoxic apoptosis inducer. Strikingly, we observed that an activated MAPK pathway promotes in several melanoma cell lines the pro-apoptotic response to genotoxic stress, and MEK inhibition reduces intrinsic apoptosis. This goes along with MEK inhibitor induced increased RAS and P-AKT levels. The protective effect of the MEK inhibitor depends on PI3K signaling, which prevents the induction of pro-apoptotic PUMA that mediates apoptosis after DNA damage. We could show that the MEK inhibitor dependent feedback loop is enabled by several factors, including EGF receptor and members of the SPRED family. The simultaneous knockdown of SPRED1 and SPRED2 mimicked the effects of MEK inhibitor such as PUMA repression and protection from apoptosis. Our data demonstrate that MEK inhibition of BRAF(V600E)-positive melanoma cells can protect from genotoxic stress, thereby achieving the opposite of the intended anti-tumorigenic effect of the combination of MEK inhibitor with inducers of intrinsic apoptosis.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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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 / pharmacology*
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Blotting, Western
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Butadienes / pharmacology
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Cell Line, Tumor
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Cell Proliferation / drug effects*
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Cisplatin / pharmacology
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Humans
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Indazoles / pharmacology
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / metabolism
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MAP Kinase Signaling System / drug effects*
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MAP Kinase Signaling System / genetics
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Melanoma / genetics
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Melanoma / metabolism
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Melanoma / pathology
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Membrane Proteins / genetics
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Membrane Proteins / metabolism
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Mitogen-Activated Protein Kinase 1 / genetics
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / genetics
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Mitogen-Activated Protein Kinase 3 / metabolism
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Mutation, Missense
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Nitriles / pharmacology
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphorylation / drug effects
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Proto-Oncogene Proteins B-raf / genetics
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Proto-Oncogene Proteins B-raf / metabolism
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Proto-Oncogene Proteins c-akt / genetics
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Proto-Oncogene Proteins c-akt / metabolism
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RNA Interference
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Repressor Proteins / genetics
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Repressor Proteins / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Sulfonamides / pharmacology
Substances
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2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine
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2-(2-chloro-4-iodophenylamino)-N-cyclopropylmethoxy-3,4-difluorobenzamide
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Benzamides
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Butadienes
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Enzyme Inhibitors
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Indazoles
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Nitriles
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Phosphoinositide-3 Kinase Inhibitors
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Repressor Proteins
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SPRED1 protein, human
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SPRED2 protein, human
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Sulfonamides
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U 0126
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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Proto-Oncogene Proteins c-akt
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MAPK1 protein, human
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Cisplatin