Abstract 1738: Pan-inhibition of super-enhancer-driven oncogenic transcription by novel synthetic ecteinascidins yields potent anti-cancer activity

Abstract Transcriptional addiction is a cancer hallmark, defined as the strong dependence of cancer cells on the high transcriptional activity of specific oncogenes promoting their proliferation and survival. This phenomenon often involves the acquisition of large clusters of enhancers known as super-enhancers (SE), which are bound by extremely abundant levels of ubiquitous transcription factors that sustain the robust oncogenic expression. Despite recent efforts to develop compounds disrupting SE-driven oncogenic expression, such as CDK7 and BRD4 inhibitors, their clinical success has been limited due to poor pharmacokinetics and short half-lives. Skin cutaneous melanoma (SKCM) serves as a valuable model for studying transcriptional addiction, as melanoma cells can dynamically shift between various cellular states through transcriptional and epigenetic reprogramming, posing a challenge for current therapeutic strategies. To address this, we developed two novel synthetic ecteinascidin derivatives of lurbinectedin, a drug approved for the treatment of advanced small cell lung cancer. Our results demonstrate that these newly developed ecteinascidins, along with the parent compound lurbinectedin, exhibit potent anti-tumor effects against melanoma, both in vitro and in mouse xenografts models resistant to current therapies, leading to reduced tumor growth and prolonged animal survival. Mechanistically, our extensive RNA-seq and chem-map assays reveal that synthetic ecteinascidins significantly suppress SE-mediated oncogene expression in melanoma cells by directly binding to and inhibiting the promoters of genes encoding ubiquitous transcription factors and coactivators that are highly enriched at oncogenic SE sites. Overall, our study provides the first evidence that the clinically approved drug, lurbinectedin, as well as its derivatives, can target and disrupt SE-dependent oncogenes, highlighting their potential as therapeutic options for cancers with transcriptionally heterogeneous landscapes where conventional therapies face significant challenges. Citation Format: Julian Obid, Max Cigrang, Maguelone Nogaret, Frédéric Coin. Pan-inhibition of super-enhancer-driven oncogenic transcription by novel synthetic ecteinascidins yields potent anti-cancer activity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1738.