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<p>High-risk sarcomas, such as metastatic and relapsed Ewing and <i>CIC</i>-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 <i>ARID1A</i> 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, <i>MCL1</i> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月21日

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  • 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

摘要

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.