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Mannarino, Laura
(2022).
DOI: https://doi.org/10.21954/ou.ro.000140dc
Abstract
Myxoid liposarcoma (MLPS) is a rare soft tissue sarcoma of the mesenchymal cells characterised by the expression of the FUS-DDIT3 oncoprotein that impairs the adipocyte differentiation. Among the available therapeutic choices for the treatment of MLPS, trabectedin has shown significant anti-tumour activity. Although prolonged treatment is well-tolerated, recurrence of the resistant tumour invariably occurs even in initially responder patients. With the aim to characterise yet unknown molecular mechanisms of trabectedin mode of action and of resistance in MLPS, we integrated genomic, transcriptomic and protein-DNA binding data from patient-derived MLPS xenograft model, ML017, and its trabectedin-resistant derivate, ML017/ET.
DNA-Seq analysis showed that acquired-resistance to trabectedin may be due to the loss of genetic material in the 4p15.2, 4p16.3 and 17q21.3 cytobands and to the consequent inhibition of the genes mapping on these regions. Integration of longitudinal RNA-Seq and ChIP-Seq data revealed a two-phases mechanism of action of trabectedin. An early phase, characterised by the cytotoxic action of trabectedin and probably independent from FUS-DDIT3 activity; a second late phase, led by the DNA-binding activity of the chimera. Indeed, trabectedin displaces FUS-DDIT3 from most of its targets and modulates the transcription of the related genes involved in processes that sustain adipocyte differentiation. To note, no such differences were observed in ML017/ET resistant model.
These results shed light on the complex mechanism of action of trabectedin in MLPS. They provide insights into the process leading to drug resistance and can be the basis for the development of novel combinatorial strategies for the treatment of MLPS.
CORE (COnnecting REpositories)
CORE (COnnecting REpositories)
