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

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.

Melanoma Persister Cells Are Tolerant to BRAF/MEK Inhibitors via ACOX1-Mediated Fatty Acid Oxidation

“…Melanoma persister cells are represented by a subpopulation of cells surviving the treatment with BRAFi/MEKi and regaining their initial sensitivity to the same drugs upon subsequent culture in a drug-free medium (Shen et al, 2019). To explore the underlying mechanisms of the metabolic state alteration in persister cells, we re-analyzed a single-cell RNA sequencing (scRNAseq) dataset of residual persister cells isolated from patient-derived melanoma xenografts grown in the presence of BRAFi/ MEKi (Rambow et al, 2018).…”

“…When grown in the absence of the EGFR inhibitor, these persister cells give rise to drug-sensitive populations (Hata et al, 2016); however, when the targeted treatment is maintained, they can serve as founders for the development of diverse acquired genetic resistance (Ramirez et al, 2016). Persister cells have been shown to arise from a dynamically fluctuating cell population that undergoes epigenetic reprogramming (Guler et al, 2017), mRNA translation reprogramming (Shen et al, 2019), and altered metabolism (Roesch et al, 2010(Roesch et al, , 2013. However, the mechanisms of metabolic alteration occurring in cancer persister cells have not been well characterized so far.…”

Gene Panel of Persister Cells as a Prognostic Indicator for Tumor Repopulation After Radiation

“…Although it was acknowledged that cancer stem cells (CSCs) largely constituted the repopulating cells, lack of unique or invariable biological properties makes the concept of CSC somewhat controversial. Accumulating studies have demonstrated that a small subpopulation of DTPs could resist the initial onslaught of cytotoxic agents for a long term until further mutations can be evolved (4,24). Some of these slow-cycling persister cells resumed proliferative potential and eventually repopulated the tumor.…”

The MNK1/2-eIF4E Axis as a Potential Therapeutic Target in Melanoma

“…In stark contrast to silvestrol and pateamine A, hippuristanol allosterically inhibits eIF4A association with mRNA and its helicase activity in both free form, as well as when eIF4A is incorporated in the eIF4F complex [151]. While the research on hippuristanol in the context of melanoma remains limited, its effects on therapy-resistant melanoma persister cells are comparable to pateamine A and silvestrol [141].…”

“…In melanoma, silvestrol has been shown to inhibit cell proliferation through increased accumulation of cells in G2/M and promotes autophagy-induced apoptosis [140]. It has been shown to both overcome vemurafenib resistance in BRAF-mutant melanoma cells and prevent the rise of therapy-resistant melanoma persister cells [141,142]. Persister cells are a category of cells that are therapy-resistant and may be key in initiating tumor relapse and acquired resistance.…”