Mechanisms of responsiveness to and resistance against trabectedin in murine models of human myxoid liposarcoma.
DNA-Seq
Data integration
Myxoid liposarcoma
PDX
RNA-Seq
Trabectedin
Journal
Genomics
ISSN: 1089-8646
Titre abrégé: Genomics
Pays: United States
ID NLM: 8800135
Informations de publication
Date de publication:
09 2021
09 2021
Historique:
received:
03
05
2021
revised:
18
06
2021
accepted:
29
07
2021
pubmed:
3
8
2021
medline:
1
4
2022
entrez:
2
8
2021
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 34339817
pii: S0888-7543(21)00306-2
doi: 10.1016/j.ygeno.2021.07.028
pii:
doi:
Substances chimiques
Trabectedin
ID0YZQ2TCP
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3439-3448Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2021. Published by Elsevier Inc.