Abstract
Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAFV600 mutant melanoma cells that tolerates exposure to BRAF and MEK inhibitors undergoes a reversible remodelling of mRNA translation that evolves in parallel with drug sensitivity. Although this process is associated with a global reduction in protein synthesis, a subset of mRNAs undergoes an increased efficiency in translation. Inhibiting the eIF4A RNA helicase, a component of the eIF4F translation initiation complex, abrogates this selectively increased translation and is lethal to persister cells. Translation remodelling in persister cells coincides with an increased N6-methyladenosine modification in the 5'-untranslated region of some highly translated mRNAs. Combination of eIF4A inhibitor with BRAF and MEK inhibitors effectively inhibits the emergence of persister cells and may represent a new therapeutic strategy to prevent acquired drug resistance.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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5' Untranslated Regions / genetics
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Adenosine / analogs & derivatives
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Adenosine / metabolism
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Antineoplastic Combined Chemotherapy Protocols / pharmacology*
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Antineoplastic Combined Chemotherapy Protocols / therapeutic use
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Cell Line, Tumor
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DNA Methylation / drug effects
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DNA Methylation / genetics
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Drug Resistance, Neoplasm / drug effects
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Drug Resistance, Neoplasm / genetics*
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Epigenesis, Genetic / drug effects
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Eukaryotic Initiation Factor-4A / antagonists & inhibitors
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Gene Expression Regulation, Neoplastic / drug effects
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Gene Expression Regulation, Neoplastic / genetics*
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Humans
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MAP Kinase Kinase Kinases / antagonists & inhibitors
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Melanoma / drug therapy*
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Melanoma / genetics
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Melanoma / pathology
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Mutation
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Protein Kinase Inhibitors / pharmacology*
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Protein Kinase Inhibitors / therapeutic use
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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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RNA Helicases / antagonists & inhibitors
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RNA, Messenger / metabolism*
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Skin Neoplasms / drug therapy*
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Skin Neoplasms / genetics
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Skin Neoplasms / pathology
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Transcription, Genetic / drug effects
Substances
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5' Untranslated Regions
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Protein Kinase Inhibitors
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RNA, Messenger
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N-methyladenosine
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BRAF protein, human
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Proto-Oncogene Proteins B-raf
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MAP Kinase Kinase Kinases
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Eukaryotic Initiation Factor-4A
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RNA Helicases
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Adenosine