Enhancing transcription-replication conflict targets ecDNA-positive cancers

  • Nature. 2024 Nov;635(8037):210-218. doi: 10.1038/s41586-024-07802-5.
Jun Tang  #  1  2 ,  Natasha E Weiser  #  1  3 ,  Guiping Wang  #  3  4 ,  Sudhir Chowdhry  5 ,  Ellis J Curtis  1  2  6 ,  Yanding Zhao  3  4  7 ,  Ivy Tsz-Lo Wong  1  2 ,  Georgi K Marinov  4 ,  Rui Li  3 ,  Philip Hanoian  8 ,  Edison Tse  5 ,  Salvador Garcia Mojica  5 ,  Ryan Hansen  5 ,  Joshua Plum  5 ,  Auzon Steffy  5 ,  Snezana Milutinovic  5 ,  S Todd Meyer  5 ,  Jens Luebeck  9 ,  Yanbo Wang  1  2  3 ,  Shu Zhang  1  2  3 ,  Nicolas Altemose  4 ,  Christina Curtis  4  10  11 ,  William J Greenleaf  4 ,  Vineet Bafna  9 ,  Stephen J Benkovic  8 ,  Anthony B Pinkerton  5 ,  Shailaja Kasibhatla  5 ,  Christian A Hassig  12 ,  Paul S Mischel  13  14 ,  Howard Y Chang  15  16  17  18
Affiliations
  • 1. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
  • 2. Sarafan ChEM-H, Stanford University, Stanford, CA, USA.
  • 3. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
  • 4. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA.
  • 5. Boundless Bio, San Diego, CA, USA.
  • 6. Medical Scientist Training Program, University of California, San Diego, La Jolla, CA, USA.
  • 7. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA.
  • 8. Department of Chemistry, Pennsylvania State University, University Park, PA, USA.
  • 9. Department of Computer Science and Engineering, University of California, San Diego, La Jolla, CA, USA.
  • 10. Department of Medicine, Stanford University School of Medicine, Stanford, CA, USA.
  • 11. Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
  • 12. Boundless Bio, San Diego, CA, USA. [email protected].
  • 13. Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 14. Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected].
  • 15. Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA. [email protected].
  • 16. Department of Genetics, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 17. Department of Dermatology, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • 18. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. [email protected].
  • # Contributed equally.
PMID: 39506153 DOI: 10.1038/s41586-024-07802-5
Abstract

Extrachromosomal DNA (ecDNA) presents a major challenge for Cancer patients. ecDNA renders tumours treatment resistant by facilitating massive oncogene transcription and rapid genome evolution, contributing to poor patient survival1-7. At present, there are no ecDNA-specific treatments. Here we show that enhancing transcription-replication conflict enables targeted elimination of ecDNA-containing cancers. Stepwise analyses of ecDNA transcription reveal pervasive RNA transcription and associated single-stranded DNA, leading to excessive transcription-replication conflicts and replication stress compared with chromosomal loci. Nucleotide incorporation on ecDNA is markedly slower, and replication stress is significantly higher in ecDNA-containing tumours regardless of Cancer type or oncogene cargo. pRPA2-S33, a mediator of DNA damage repair that binds single-stranded DNA, shows elevated localization on ecDNA in a transcription-dependent manner, along with increased DNA double strand breaks, and activation of the S-phase checkpoint kinase, Chk1. Genetic or pharmacological Chk1 inhibition causes extensive and preferential tumour cell death in ecDNA-containing tumours. We advance a highly selective, potent and bioavailable oral Chk1 Inhibitor, BBI-2779, that preferentially kills ecDNA-containing tumour cells. In a gastric Cancer model containing FGFR2 amplified on ecDNA, BBI-2779 suppresses tumour growth and prevents ecDNA-mediated acquired resistance to the pan-FGFR inhibitor infigratinib, resulting in potent and sustained tumour regression in mice. Transcription-replication conflict emerges as a target for ecDNA-directed therapy, exploiting a synthetic lethality of excess to treat Cancer.

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