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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Note that Comp = PM54.

ORGANISM(S): Homo sapiens

PROVIDER: GSE256103 | GEO | 2024/02/23

REPOSITORIES: GEO

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [RNA-Seq]

Project description:Melanoma cells exhibit a dynamic capacity for transitioning through various cellular states. This intricate biological trait poses significant challenges to current therapeutics approaches, emphasizing the urgent need for innovative treatment strategies. Here, we initially demonstrated the efficacy of Lurbinectedin, a synthetic ecteinascidin derived from marine sources, against melanoma cells, irrespective of their driver mutations or phenotypic manifestations. Subsequently, we designed and evaluated two derivatives of Lurbinectedin, termed Ecubectedin and PM54(Comp IA), both of which fully recapitulate the cytotoxic effects of Lurbinectedin in vitro and might present benefits versus the original compound. These derivatives also exert a noteworthy in vivo impact on tumor growth and animal survival, inducing apoptosis in melanoma cells. Mechanistically, our investigations revealed that ecteinascidins strongly inhibit oncogenic super-enhancer-mediated gene expression by a three-pronged mechanism. Firstly, the binding to the promoters of lineage-specific master transcription factors and the disruption of their associated auto-regulatory circuits, secondly, the binding and inhibition of genes encoding ubiquitous transcription factors/coactivators, heavily enriched at oncogenic SEs, and thirdly, the direct drug-binding to these regulatory elements, seemingly hampering the assembly of transcriptional condensates, all likely work in tandem to disrupt oncogene expression. These findings underscore the potential of ecteinascidins as promising therapeutics for melanoma and potentially other transcriptionally-addicted cancers.

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [Cut & Tag, ATAC-Seq]

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription

Project description:Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription

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Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [RNA-Seq]

Project description:Novel synthetic ecteinascidins exhibit potent anti-melanoma activity by targeting super-enhancer-driven oncogenic transcription [RNA-Seq]

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Pharmacological Targeting of Casein Kinase 1δ Suppresses Oncogenic NRAS-Driven Melanoma

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