Myxoid liposarcoma (MLPS) is a rare soft-tissue sarcoma characterised by the expression of FUS-DDIT3 chimera. Trabectedin has shown significant clinical anti-tumour activity against MLPS. To characterise the molecular mechanism of trabectedin sensitivity and of resistance against it, we integrated genomic and transcriptomic data from treated mice bearing ML017 or ML017/ET, two patient-derived MLPS xenograft models, sensitive to and resistant against trabectedin, respectively.

Longitudinal RNA-Seq analysis of ML017 showed that trabectedin acts mainly as a transcriptional regulator: 15 days after the third dose trabectedin modulates the transcription of 4883 genes involved in processes that sustain adipocyte differentiation. No such differences were observed in ML017/ET. Genomic analysis showed that prolonged treatment causes losses in 4p15.2, 4p16.3 and 17q21.3 cytobands leading to acquired-resistance against the drug.

The results dissect the complex mechanism of action of trabectedin and provide the basis for novel combinatorial approaches for the treatment of MLPS that could overcome drug-resistance.

粘液样脂肪肉瘤 (MLPS) 是一种罕见的软组织肉瘤，其特征是 FUS-DDIT3 嵌合体的表达。Trabectedin 对 MLPS 显示出显着的临床抗肿瘤活性。为了表征曲贝替丁敏感性和耐药性的分子机制，我们整合了来自携带 ML017 或 ML017/ET 的治疗小鼠的基因组和转录组数据，这两种患者衍生的 MLPS 异种移植模型分别对曲贝替定敏感和耐药。

ML017 的纵向 RNA-Seq 分析表明，曲贝替定主要充当转录调节剂：第三次给药后 15 天，曲贝替定调节参与维持脂肪细胞分化过程的 4883 个基因的转录。在 ML017/ET 中没有观察到这种差异。基因组分析表明，长期治疗会导致4p15.2、4p16.3和17q21.3细胞带丢失，从而导致对药物的获得性耐药。

结果剖析了曲贝替定的复杂作用机制，并为治疗可克服耐药性的 MLPS 的新组合方法提供了基础。