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

Shensi Shen (1) , Sara Faouzi (2, 1) , Amandine Bastide (3) , Sylvain Martineau (4) , Hélène Malka-Mahieu , Yu Fu (5, 1) , Xiaoxiao Sun , Christine Mateus (6) , Emilie Routier (7) , Severine Roy , Laurent Désaubry (8) , Fabrice André (9, 1) , Alexander Eggermont (10) , Alexandre David (3) , Jean-Yves Scoazec (11, 12) , Stéphan Vagner , Caroline Robert (13, 1, 7)

1 U981 - Biomarqueurs prédictifs et nouvelles stratégies moléculaires en thérapeutique anticancéreuse
2 UPJV - Université de Picardie Jules Verne
3 IGF - Institut de Génomique Fonctionnelle
4 Stress génotoxiques et cancer
5 NJU - Nanjing University
6 DISSPO - Département Interdisciplinaire de Soins de Support aux Patients en Onco-hématologie [Gustave Roussy]
7 Oncologie dermatologique
8 LBM UMR 7203 - Laboratoire des biomolécules
9 Pathologie mammaire
10 UMR 1015 - Immunologie des tumeurs et immunothérapie
11 UP11 UFR Médecine - Université Paris-Sud - Paris 11 - Faculté de médecine
12 Pathologie morphologique
13 U362 - Hematopoïèse et Cellules Souches

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.

Domaines: Sciences du Vivant [q-bio]; Cancer

Shensi Shen, Sara Faouzi, Amandine Bastide, Sylvain Martineau, Hélène Malka-Mahieu, et al.. An epitranscriptomic mechanism underlies selective mRNA translation remodelling in melanoma persister cells. Nature Communications, 2019, 10 (1), ⟨10.1038/s41467-019-13360-6⟩. ⟨hal-02418638⟩