0086-571-89925085
Ilaria Craparotta 1,#, Laura Mannarino 2,3,#, Riccardo Zadro 2,3,#, Sara Ballabio 4, Sergio Marchini 3, Giulio Pavesi 5, Marta Russo 6, Salvatore Lorenzo Renne 2,7, Marina Meroni 1, Marianna Ponzo 1, Ezia Bello 1, Roberta Sanfilippo 8, Paolo G Casali 8, Maurizio D’Incalci 2,3,✉, Roberta Frapolli 1
PMCID: PMC11590625 PMID: 39587691
The marine drug trabectedin has shown unusual effectiveness in the treatment of myxoid liposarcoma (MLPS), a liposarcoma characterized by the expression of the FUS-DDIT3 chimera. Trabectedin elicits a significant transcriptional response in MLPS resulting in cellular depletion and reactivation of adipogenesis. However, the role of the chimeric protein in the mechanism of action of the drug is not entirely understood. FUS-DDIT3-specific binding sites were assessed through Chromatin Immunoprecipitation Sequencing (ChIP-Seq). Trabectedin-induced effects were studied on pre-established patient-derived xenograft models of MLPS, one sensitive to (ML017) and one resistant against (ML017ET) trabectedin at different time points (24 and 72 h, 15 days). Data were integrated with RNA-Seq from the same models. Through ChIP-Seq, here we demonstrate that trabectedin inhibits the binding of FUS-DDIT3 to its target genes, restoring adipocyte differentiation in a patient-derived xenograft model of MLPS sensitive to trabectedin. In addition, complementary RNA-Seq data on the same model demonstrates a two-phase effect of trabectedin, characterized by an initial FUS-DDIT3-independent cytotoxicity, followed by a transcriptionally active pro-differentiation phase due to the long-lasting detachment of the chimera from the DNA. Interestingly, in a trabectedin-resistant MLPS model, the effect of trabectedin on FUS-DDIT3 rapidly decreased over time, and prolonged treatment was no longer able to induce any transcription or post-transcriptional modifications. These findings explain the unusual mechanism underlying trabectedin's effectiveness against MLPS by pinpointing the chimera's role in inducing the differentiation block responsible for MLPS pathogenesis. Additionally, the findings hint at a potential mechanism of resistance acquired in vivo. The online version contains supplementary material available at 10.1186/s13046-024-03228-z.Abstract
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Trabectedin (also known as ecteinascidin 743 or ET-743, trade name Yondelis) is an antitumor chemotherapy drug sold by Pharma Mar S.A. and Johnson and Johnson under the brand name Yondelis. It is approved for use in Europe, Russia, and South Korea for the treatment of advanced soft-tissue sarcoma. It is also undergoing clinical trials for the treatment of breast, prostate, and paediatric sarcomas. The European Commission and the U.S. Food and Drug Administration (FDA) have granted orphan drug status to trabectedin for soft-tissue sarcomas and ovarian cancer.
