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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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Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid cancer

Project description:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancy and accounts for the majority of thyroid cancer-related deaths. Despite intensive research, there remains no effective treatment for patients with ATC. Here, we identify THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid cancer (PTC) cells, are exceptionally sensitive to CDK7 inhibition. Analyzing both gene expression profiles and super enhancer (SE) features reveals that the SE-mediated oncogenic transcriptional amplification renders the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays discovers a number of novel cancer genes of ATC, including PPP1R15A, SMG9 and KLF2. Inhibition of PPP1R15A with Guanabenz (GBZ) or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, GBZ or THZ1 treatment sensitizes ATC cells to conventional chemotherapy. Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

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Targeting of Super-Enhancer-Associated Oncogenic Transcription in MYCN-driven tumor cells by CDK7 inhibition [Gene Expression]

Project description:Global gene expression after CDK7 inhibition by THZ1 Global gene expression after genetic knockdown or overexpression of MYCN

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