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

Shensi Shen1, Sara Faouzi2,3, Amandine Bastide4

  • 1INSERM U981, Gustave Roussy Cancer Campus, Villejuif, France. SHENSI.SHEN@gustaveroussy.fr.

Nature Communications
|December 18, 2019
PubMed

Insights

Cancer persister cells can survive drug treatment by altering protein synthesis. Targeting the eIF4A RNA helicase with inhibitors can eliminate these cells, offering a new strategy against drug resistance and relapse.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Cancer persister cells survive anticancer drugs, leading to acquired resistance and relapse.
  • BRAF-mutant melanoma cells exhibit drug tolerance to BRAF and MEK inhibitors.

Purpose of the Study:

  • To investigate the mechanisms of drug tolerance in cancer persister cells.
  • To identify therapeutic strategies to overcome drug resistance in melanoma.

Main Methods:

  • Analysis of mRNA translation remodeling in drug-tolerant BRAF-mutant melanoma cells.
  • Inhibition of the eIF4A RNA helicase and its effect on persister cells.
  • Assessment of N6-methyladenosine modification in mRNA.

Main Results:

  • Drug-tolerant persister cells undergo reversible mRNA translation remodeling with selective translation efficiency increase.
  • Inhibiting eIF4A RNA helicase abrogates selective mRNA translation and is lethal to persister cells.
  • Increased N6-methyladenosine modification is observed in highly translated mRNAs within persister cells.

Conclusions:

  • Targeting eIF4A in combination with BRAF and MEK inhibitors can prevent persister cell emergence.
  • This combination therapy may offer a novel strategy to prevent acquired drug resistance in melanoma.

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