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

Shensi Shen (), Sara Faouzi, Amandine Bastide, Sylvain Martineau, Hélène Malka-Mahieu, Yu Fu, Xiaoxiao Sun, Christine Mateus, Emilie Routier, Severine Roy, Laurent Desaubry, Fabrice André, Alexander Eggermont, Alexandre David, Jean-Yves Scoazec, Stéphan Vagner () and Caroline Robert ()
Additional contact information
Shensi Shen: Gustave Roussy Cancer Campus
Sara Faouzi: Gustave Roussy Cancer Campus
Amandine Bastide: University Montpellier
Sylvain Martineau: Institut Curie, PSL Research University, CNRS UMR3348
Hélène Malka-Mahieu: Institut Curie, PSL Research University, CNRS UMR3348
Yu Fu: Gustave Roussy Cancer Campus
Xiaoxiao Sun: University of California
Christine Mateus: Gustave Roussy Cancer Campus
Emilie Routier: Gustave Roussy Cancer Campus
Severine Roy: Gustave Roussy Cancer Campus
Laurent Desaubry: CNRS-Strasbourg University
Fabrice André: Gustave Roussy Cancer Campus
Alexander Eggermont: Université Paris-Sud, Université Paris-Saclay
Alexandre David: University Montpellier
Jean-Yves Scoazec: Université Paris-Sud, Université Paris-Saclay
Stéphan Vagner: Institut Curie, PSL Research University, CNRS UMR3348
Caroline Robert: Gustave Roussy Cancer Campus

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13360-6

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