Patient-derived tumoroids from CIC::DUX4 rearranged sarcoma identify MCL1 as a therapeutic target
- Willemijn Breunis
- Eva Brack
- Anna C. Ehlers
- Ingrid Bechtold
- Samanta Kisele
- Jakob Wurth
- Lieke Mous
- Dorita Zabele
- Fabio Steffen
- Felina Zahnow
- Christian Britschgi
- Lorenz Bankel
- Christian Rothermundt
- Cornelia Vetter
- Daniel Müller
- Sander Botter
- Chantal Pauli
- Peter Bode
- Beate Rinner
- Jean-Pierre Bourquin
- Jochen Roessler
- Thomas G. P. Grünewald
- Beat W. Schäfer
- Didier Surdez
- Marco Wachtel
2025-08-21
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.