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Extrachromosomal DNA-driven oncogene dosage heterogeneity promotes rapid adaptation to therapy in MYCN-amplified cancers

Authors

  • Giulia Montuori
  • Fengyu Tu
  • Di Qin
  • Rachel Schmargon
  • Elias Rodriguez-Fos
  • Konstantin Helmsauer
  • Hui Hui
  • Susmita Mandal
  • Karin Purshouse
  • Lara Fankhänel
  • Bartolomeo Bosco
  • Bastiaan Spanjaard
  • Hannah Seyboldt
  • Laura Grunewald
  • Matthias Jürgen Schmitt
  • Dennis Gürgen
  • Viktoria Buck
  • Mathias T Rosenfeldt
  • Frank P.B. Dubois
  • Simon Schallenberg
  • Annika Lehmann
  • Jessica Theißen
  • Sabine Taschner-Mandl
  • Arend Koch
  • Patrick Hundsdoerfer
  • Annette Künkele
  • Angelika Eggert
  • Matthias Fischer
  • Gaetano Gargiulo
  • Teresa G Krieger
  • Lukas Chavez
  • Fabian Coscia
  • Benjamin Werner
  • Weini Huang
  • Anton G. Henssen
  • Jan R. Dörr

Journal

  • Cancer Discovery

Citation

  • Cancer Discov OF1-OF24

Abstract

  • Extrachromosomal DNA (ecDNA) amplification enhances intercellular oncogene dosage variability and accelerates tumor evolution by violating foundational principles of genetic inheritance through its asymmetric mitotic segregation. Spotlighting highrisk neuroblastoma, we demonstrate how ecDNA amplification undermines the clinical efficacy of current therapies in cancers with extrachromosomal MYCN amplification. Integrating theoretical models of oncogene copy number–dependent fitness with single-cell ecDNA quantification and phenotype analyses, we reveal that ecDNA copy-number heterogeneity drives phenotypic diversity and determines treatment sensitivity through mechanisms unattainable by chromosomal oncogene amplification. We demonstrate that ecDNA copy number directly influences cell fate decisions in cancer cell lines, patient-derived xenografts, and primary neuroblastomas, illustrating how extrachromosomal oncogene dosage–driven phenotypic diversity offers a strong evolutionary advantage under therapeutic pressure. Furthermore, we identify senescent cells with reduced ecDNA copy numbers as a source of treatment resistance in neuroblastomas and outline a strategy for their targeted elimination to improve the treatment of MYCN-amplified cancers. SIGNIFICANCE: ecDNA-driven tumor genome evolution provides a major challenge to curative cancer therapies. We demonstrate that ecDNA copy-number dynamics drives treatment resistance by promoting oncogene dosage–dependent phenotypic heterogeneity in MYCN-amplified cancers. Exploiting phenotype-specific vulnerabilities of ecDNA cells, therefore, presents a powerful strategy to overcome treatment resistance.


DOI

doi:10.1158/2159-8290.CD-24-1738