Journal Article

DKFZ-2025-01744

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target.

Breunis, W. ; Brack, E. ; Ehlers, A. C.DKFZ* ; Bechtold, I. ; Kisele, S. ; Wurth, J. ; Mous, L. ; Zabele, D. ; Steffen, F. ; Zahnow, F.DKFZ* ; Britschgi, C. ; Bankel, L. ; Rothermundt, C. ; Vetter, C. ; Müller, D. ; Botter, S. ; Pauli, C. ; Bode, P. ; Rinner, B. ; Bourquin, J.-P. ; Roessler, J. ; Grünewald, T.DKFZ* ; Schäfer, B. W. ; Surdez, D. ; Wachtel, M.

2025
Springer Nature [London]

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.

Keyword(s): Humans (MeSH) ; Myeloid Cell Leukemia Sequence 1 Protein: genetics (MeSH) ; Myeloid Cell Leukemia Sequence 1 Protein: metabolism (MeSH) ; Myeloid Cell Leukemia Sequence 1 Protein: antagonists & inhibitors (MeSH) ; Animals (MeSH) ; Oncogene Proteins, Fusion: genetics (MeSH) ; Oncogene Proteins, Fusion: metabolism (MeSH) ; Mice (MeSH) ; Sarcoma: genetics (MeSH) ; Sarcoma: drug therapy (MeSH) ; Sarcoma: pathology (MeSH) ; Sarcoma: metabolism (MeSH) ; Sarcoma, Ewing: genetics (MeSH) ; Sarcoma, Ewing: drug therapy (MeSH) ; Sarcoma, Ewing: pathology (MeSH) ; Xenograft Model Antitumor Assays (MeSH) ; Cell Line, Tumor (MeSH) ; Apoptosis: drug effects (MeSH) ; Apoptosis: genetics (MeSH) ; Antineoplastic Agents: pharmacology (MeSH) ; Female (MeSH) ; Gene Rearrangement (MeSH) ; Repressor Proteins (MeSH) ; Myeloid Cell Leukemia Sequence 1 Protein ; MCL1 protein, human ; Oncogene Proteins, Fusion ; CIC protein, human ; CIC-DUX4 fusion protein, human ; Antineoplastic Agents ; Repressor Proteins

---

Contributing Institute(s):

1. Translationale Pädiatrische Sarkomforschung (B410)
2. DKTK HD zentral (HD01)

Research Program(s):

1. 312 - Funktionelle und strukturelle Genomforschung (POF4-312) (POF4-312)

Appears in the scientific report 2025

---

Database coverage:
; ; ; Article Processing Charges ; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Agriculture, Biology and Environmental Sciences ; Current Contents - Life Sciences ; Current Contents - Physical, Chemical and Earth Sciences ; DOAJ Seal ; Essential Science Indicators ; Fees ; IF >= 15 ; JCR ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection ; Zoological Record

---