Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target PMID: 40841513

ADC Targets in Oncology

2026-04-10

Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target

Nat Commun. 2025 Aug 21;16(1):7688. doi: 10.1038/s41467-025-62629-6.

Willemijn Breunis ^# ¹ , Eva Brack ^# ² , Anna C Ehlers ³ ⁴ ⁵ ⁶ , Ingrid Bechtold ¹ , Samanta Kisele ¹ , Jakob Wurth ¹ , Lieke Mous ⁷ , Dorita Zabele ⁷ , Fabio Steffen ¹ , Felina Zahnow ³ , Christian Britschgi ⁸ ⁹ , Lorenz Bankel ⁸ , Christian Rothermundt ¹⁰ , Cornelia Vetter ¹¹ , Daniel Müller ¹² , Sander Botter ¹³ , Chantal Pauli ¹⁴ , Peter Bode ¹⁴ , Beate Rinner ¹⁵ , Jean-Pierre Bourquin ¹ , Jochen Roessler ² , Thomas G P Grünewald ³ ⁴ ⁵ ¹⁶ , Beat W Schäfer ¹⁷ , Didier Surdez ¹⁸ , Marco Wachtel ¹⁹

Affiliations

1. Department of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland.
2. Division of Pediatric Hematology/Oncology, Department of Pediatrics, Inselspital, Bern University Hospital, Bern, Switzerland.
3. Hopp-Children's Cancer Center (KiTZ), Heidelberg, Germany.
4. Division of Translational Pediatric Sarcoma Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany.
5. National Center for Tumor Diseases (NCT), NCT Heidelberg, a partnership between DKFZ and Heidelberg University Hospital, Heidelberg, Germany.
6. Medical Faculty, Ruprecht-Karls-University, Heidelberg, Germany.
7. Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland.
8. Department of Medical Oncology and Hematology, University Hospital Zurich, Comprehensive Cancer Center Zurich, Zurich, Switzerland.
9. Medical Oncology and Hematology, Cantonal Hospital Winterthur, Winterthur, Switzerland.
10. Department of Medical Oncology and Hematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.
11. Division of Pediatric Hematology/Oncology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
12. University Sarcoma Center Zürich (CCCZ), Balgrist University Hospital, University of Zurich, Zurich, Switzerland.
13. Swiss Center for Musculoskeletal Biobanking, Balgrist Campus AG, Zurich, Switzerland.
14. Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
15. Division of Biomedical Research, Medical University of Graz, Graz, Austria.
16. Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany.
17. Department of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland. [email protected].
18. Balgrist University Hospital, Faculty of Medicine, University of Zurich (UZH), Zurich, Switzerland. [email protected].
19. Department of Oncology and Children's Research Center, University Children's Hospital, University of Zurich, Zurich, Switzerland. [email protected].
# Contributed equally.

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.