An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells

Author:

Shen ShensiORCID,Faouzi Sara,Bastide AmandineORCID,Martineau Sylvain,Malka-Mahieu Hélène,Fu Yu,Sun Xiaoxiao,Mateus Christine,Routier Emilie,Roy Severine,Desaubry Laurent,André FabriceORCID,Eggermont Alexander,David Alexandre,Scoazec Jean-YvesORCID,Vagner StéphanORCID,Robert Caroline

Abstract

AbstractCancer 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.

Funder

Fondation ARC pour la Recherche sur le Cancer

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry

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