Pan-inhibition of super-enhancer-driven oncogenic transcription by next-generation synthetic ecteinascidins yields potent anti-cancer activity

Max Cigrang, Julian Obid, Maguelone Nogaret, Léane Seno, Tao Ye, Guillaume Davidson, Philippe Catez, Pietro Berico, Clara Capelli, Clara Marechal, Amélie Zachayus, Clémence Elly, Marie Jose Guillen Navarro, Marta Martinez Diez, Gema Santamaria Nunez, Tsai-Kun Li, Emmanuel Compe, Pablo Avilés, Irwin Davidson, Jean-Marc Egly, Carmen Cuevas and Frédéric Coin ()
Additional contact information
Max Cigrang: C.U. Equipe Labélisée Ligue contre le Cancer
Julian Obid: C.U. Equipe Labélisée Ligue contre le Cancer
Maguelone Nogaret: C.U. Equipe Labélisée Ligue contre le Cancer
Léane Seno: C.U. Equipe Labélisée Ligue contre le Cancer
Tao Ye: C.U. Equipe Labélisée Ligue contre le Cancer
Guillaume Davidson: C.U. Equipe Labélisée Ligue contre le Cancer
Philippe Catez: C.U. Equipe Labélisée Ligue contre le Cancer
Pietro Berico: C.U. Equipe Labélisée Ligue contre le Cancer
Clara Capelli: C.U. Equipe Labélisée Ligue contre le Cancer
Clara Marechal: C.U. Equipe Labélisée Ligue contre le Cancer
Amélie Zachayus: C.U. Equipe Labélisée Ligue contre le Cancer
Clémence Elly: C.U. Equipe Labélisée Ligue contre le Cancer
Marie Jose Guillen Navarro: PharmaMar SA
Marta Martinez Diez: PharmaMar SA
Gema Santamaria Nunez: PharmaMar SA
Tsai-Kun Li: National Taiwan University
Emmanuel Compe: C.U. Equipe Labélisée Ligue contre le Cancer
Pablo Avilés: PharmaMar SA
Irwin Davidson: C.U. Equipe Labélisée Ligue contre le Cancer
Jean-Marc Egly: C.U. Equipe Labélisée Ligue contre le Cancer
Carmen Cuevas: PharmaMar SA
Frédéric Coin: C.U. Equipe Labélisée Ligue contre le Cancer

Nature Communications, 2025, vol. 16, issue 1, 1-21

Abstract: Abstract The plasticity of cancer cells facilitates their ability to adopt heterogeneous differentiation states, posing a significant challenge to therapeutic interventions. Specific gene expression programs, driven in part by super-enhancers (SEs), underlie cancer cell states. Here we successfully inhibit SE-driven transcription in phenotypically distinct metastatic melanoma cells using next-generation synthetic ecteinascidins. Through functional genomic methodologies, we demonstrate that these compounds inhibit the expression of genes encoding lineage-specific or ubiquitous transcription factors/coactivators by selectively targeting the CpG-rich sequences within their promoters and/or enhancers. This prevents the formation of transcription factor/coactivator condensates necessary for SE-dependent gene expression. Consequently, these compounds exhibit cytotoxic activity across distinct subpopulations of metastatic melanoma cells and inhibit tumor proliferation, including those resistant to current therapies. These findings extend to other cancers, like small cell lung cancer, recently approved for ecteinascidin-based treatment. Overall, our study provides preclinical proof that pan-inhibition of SE-dependent genes with synthetic ecteinascidins is a promising therapeutic approach for tumors with heterogeneous transcriptional landscapes.

Date: 2025
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DOI: 10.1038/s41467-024-55667-z

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