Erratum: A stress-induced early innate response causes multidrug tolerance in melanoma

Epigenetics in Melanoma Development and Drug Resistance

“…Elevated EGFR and PDGFRβ levels have been shown to be reversible after discontinuing BRAF and MEK inhibitor treatment, while expression of EGFR or treatment with TGF-β resulted in a slow cycling drug-resistant phenotype [72]. This observation reflects findings by our group [73] and others [74,75] of reversible multidrug-tolerant slow-cycling state following stressors like drug treatment. Beside failure of BRAF inhibition, a recent study found that dynamic and recurrent non-genomic alterations following chronic BRAF inhibitor treatment also affect tumor immunity possibly resulting in cross resistance to anti PD-1 therapy [76].…”

“…KDM5B high cells have been found to be enriched upon drug treatment and resemble a slow cycling drug-tolerant state in melanoma as shRNA-mediated knockdown of KDM5B increased sensitivity to different drugs [90]. In accordance with the dynamic nature of KDM5A and KDM5B positive subpopulations, we have observed that chronic exposure to external stressors, rather than specific drug treatment, initiates an innate cellular response whereupon cells adopt a slow cycling, multidrug-tolerant phenotype [91]. Continuous exposure of melanoma cells to sub lethal BRAF inhibitor concentrations for 12 days initiated a cellular transformation and not the selection of a pre-existing subpopulation, which resulted in a slow cycling, mainly G1 arrested phenotype.…”

“…As demonstrated for the KDM5A high subpopulation [74], IDTCs re-gained drug sensitivity upon 7 days of drug withdrawal. On the molecular level IDTCs displayed elevated expression of drug efflux genes including ABCB5, ABCA5, ABCB8 and ABCB4, as well as melanoma stem cell markers NGFR, SOX10, CD44, SOX2 and SOX4, suggesting the transition into an undifferentiated state [91]. These molecular changes were accompanied by a profound decrease of histone marks H3K4me3, H3K27me3 that were decreased and H3K9me3, which was increased.…”

“…These molecular changes were accompanied by a profound decrease of histone marks H3K4me3, H3K27me3 that were decreased and H3K9me3, which was increased. Accordingly, expression of several histone-modifying enzymes including the H3K27-specific demethylases, KDM6A, KDM6B and the H3K4-specific demethylases, KDM1B, KDM5A and KDM5B was increased at the IDTC state [91]. Interestingly, a similar transition into an H3K4me3 low /H3K27me3 low /H3K9me3 high state was triggered by hypoxia and nutrient starvation and IDTCs generated by these stressors exhibited tolerance to BRAF inhibitors or cisplatin treatment, suggesting an epigenetically regulated drug-independent generic stress response that allows cells to cope with difficult environmental conditions [91].…”

“…Accordingly, expression of several histone-modifying enzymes including the H3K27-specific demethylases, KDM6A, KDM6B and the H3K4-specific demethylases, KDM1B, KDM5A and KDM5B was increased at the IDTC state [91]. Interestingly, a similar transition into an H3K4me3 low /H3K27me3 low /H3K9me3 high state was triggered by hypoxia and nutrient starvation and IDTCs generated by these stressors exhibited tolerance to BRAF inhibitors or cisplatin treatment, suggesting an epigenetically regulated drug-independent generic stress response that allows cells to cope with difficult environmental conditions [91]. Similar to our proposed IDTCs, a slow cycling, reversible NGFR high state that displays features of de-differentiation has also been described, which has been shown to be susceptible to inhibition of epigenetic modifiers as bromodomain inhibitors, that block recognition of acetylated histones, suppressed the slowly cycling NGFR high state [92].…”