Journal
NATURE COMMUNICATIONS
Volume 10, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-13360-6
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Funding
- INSERM, CNRS, Gustave Roussy
- Rising Tide Foundation for Clinical Cancer Research (RTFCCR) [565840]
- Fondation ARC pour la Recherche sur le Cancer [PJA20161204588]
- Ligue Nationale Contre le Cancer (Equipe labellisee)
- Institut National du Cancer [2013-1-MEL-01-ICR-1]
- Collectif Ensemble contre le melanome
- Les Sites de recherche Integres sur le Cancer (SIRIC) label Gustave Roussy
- Melanoma Research Alliance (MRA)
- Institut Curie
- Association Vaincre le Melanome
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Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Here we show that a subpopulation of BRAF(V600) 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.
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