Pan-inhibition of super-enhancer-driven oncogenic transcription by next-generation synthetic ecteinascidins yields potent anti-cancer activity.
Journal
Nature communications
Journal Volume
16
Journal Issue
1
Start Page
Article number 512
ISSN
2041-1723
Date Issued
2025-01-08
Author(s)
Cigrang, Max
Obid, Julian
Nogaret, Maguelone
Seno, Léane
Ye, Tao
Davidson, Guillaume
Catez, Philippe
Berico, Pietro
Capelli, Clara
Marechal, Clara
Zachayus, Amélie
Elly, Clémence
Guillen Navarro, Marie Jose
Martinez Diez, Marta
Santamaria Nunez, Gema
Compe, Emmanuel
Avilés, Pablo
Davidson, Irwin
Egly, Jean-Marc
Cuevas, Carmen
Coin, Frédéric
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.
Type
journal article