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.
Highlights
Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse
One hundred per cent of tested single cellderived sub-clones (n = 5) contained surviving persister cells (Supplementary Fig. 1a and Methods), excluding pre-existing genetic heterogeneity. These results indicate that the persistent state represents a major survival mechanism against BRAFV600E inhibitor (BRAFi)/MEK inhibitor (MEKi) treatment in melanoma
Compared with parental A375 cells (Par) that had never been exposed to the treatment, persister cells (Per) showed strong tolerance to a second challenge of BRAFi/MEKi treatment applied 1 day after treatment withdrawal as shown by viability (Fig. 1a, b) and caspase-3/7 activity assays (Supplementary Fig. 1b)
Summary
Cancer persister cells tolerate anticancer drugs and serve as the founders of acquired resistance and cancer relapse. Recent studies have shown that a small fraction of cancer cells that survive initial treatment (e.g., anti-epidermal growth factor receptor (EGFR) erlotinib in non-small cell lung cancer) eventually regain their sensitivity to the same drug after a “drug holiday”[7,8] This reversible drugtolerant state putatively allows those “persister” cells to survive the initial onslaught of drug before evolving under selective pressure until resistance-conferring permanent genetic mutations emerge. We show that BRAFV600E melanoma cells undergoes a reversible mRNA translational reprogramming, by upregulating a subset of mRNAs that encodes epigenetic regulators and mammalian target of rapamycin (mTOR) pathwayrelated proteins The upregulation of this subset of mRNAs require the RNA helicase eIF4A, whose inhibition selectively kills the melanoma persister cells. Inhibition of eIF4A decreases the association of m6A-modified mRNAs with polysomes and prevents the emergence of BRAFi/MEKiresistant clones
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