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SHR Neuro Krebs Kardio Lipid Stoffw Microb

Breunis, W; Brack, E; Ehlers, AC; Bechtold, I; Kisele, S; Wurth, J; Mous, L; Zabele, D; Steffen, F; Zahnow, F; Britschgi, C; Bankel, L; Rothermundt, C; Vetter, C; Müller, D; Botter, S; Pauli, C; Bode, P; Rinner, B; Bourquin, JP; Roessler, J; Grünewald, TGP; Schäfer, BW; Surdez, D; Wachtel, M.
Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target.
Nat Commun. 2025; 16(1):7688 Doi: 10.1038/s41467-025-62629-6 [OPEN ACCESS]
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Autor*innen der Med Uni Graz:
Rinner Beate
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Abstract:
High-risk sarcomas, such as metastatic and relapsed Ewing and CIC-rearranged sarcoma, still have a poor prognosis despite intensive therapeutic regimens. Precision medicine approaches offer hope, and ex vivo drug response profiling of patient-derived tumor cells emerges as a promising tool to identify effective therapies for individual patients. Here, we establish ex vivo culture conditions to propagate Ewing sarcoma and CIC::DUX4 sarcoma as tumoroids. These models retain their original molecular and functional characteristics, including recurrent ARID1A mutations in CIC::DUX4 sarcoma, and serve as tumor avatars for large-scale drug testing. Screening a large drug library on a small living biobank of such tumors not only reveals distinct differences in drug response between the two entities, but also identifies a dependency of CIC::DUX4 sarcoma cells on MCL1. Mechanistically, MCL1 is identified as a direct transcriptional target of the CIC::DUX4 fusion oncogene. Genetic and pharmacological inhibition of MCL1 induces rapid apoptosis in CIC::DUX4 sarcoma cells and inhibits tumor growth in a xenograft model. Thus, MCL1 represents a potential therapeutic target for CIC::DUX4 sarcoma. Overall, our study highlights the feasibility of drug response profiling for individual sarcoma cases and suggests that further clinical assessments of its benefit are warranted.
Find related publications in this database (using NLM MeSH Indexing)
Humans - administration & dosage
Myeloid Cell Leukemia Sequence 1 Protein - genetics, metabolism, antagonists & inhibitors
Animals - administration & dosage
Oncogene Proteins, Fusion - genetics, metabolism
Mice - administration & dosage
Sarcoma - genetics, drug therapy, pathology, metabolism
Sarcoma, Ewing - genetics, drug therapy, pathology
Xenograft Model Antitumor Assays - administration & dosage
Cell Line, Tumor - administration & dosage
Apoptosis - drug effects, genetics
Antineoplastic Agents - pharmacology
Female - administration & dosage
Gene Rearrangement - administration & dosage
Repressor Proteins - administration & dosage

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