Enhancing transcription–replication conflict targets ecDNA-positive cancers
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 survival<sup>1-7</sup>. 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.
Authors
- Georgi K. Marinov (ORCID: https://orcid.org/0000-0003-1822-7273)
- Edison Tse (ORCID: https://orcid.org/0000-0002-6252-2731)
- Sudhir Chowdhry (ORCID: https://orcid.org/0000-0001-6704-1550)
- Anthony B. Pinkerton (ORCID: https://orcid.org/0000-0003-4571-152X)
- Vineet Bafna (ORCID: https://orcid.org/0000-0002-5810-6241)
- Christian A. Hassig (ORCID: https://orcid.org/0009-0005-7431-9166)
- Christina N. Curtis (ORCID: https://orcid.org/0000-0003-0166-3802)
- Ellis J. Curtis (ORCID: https://orcid.org/0000-0003-3751-9968)
- Howard Y. Chang (ORCID: https://orcid.org/0000-0002-9459-4393)
- Paul S. Mischel (ORCID: https://orcid.org/0000-0002-4560-2211)
- Guiping Wang (ORCID: https://orcid.org/0000-0002-6347-0419)
- Ivy Tsz-Lo Wong (ORCID: https://orcid.org/0000-0002-9761-3422)
- Philip Hanoian
- Auzon Steffy
- Yanding Zhao (ORCID: https://orcid.org/0000-0002-6882-4888)
- Stephen J. Benkovic (ORCID: https://orcid.org/0000-0003-3680-3481)
- Nicolas Altemose (ORCID: https://orcid.org/0000-0002-7231-6026)
- Snezana Milutinovic
- Jens Luebeck (ORCID: https://orcid.org/0000-0003-4391-979X)
- William J. Greenleaf (ORCID: https://orcid.org/0000-0003-1409-3095)
- Salvador Garcia Mojica
- Natasha E. Weiser (ORCID: https://orcid.org/0000-0001-9971-2961)
- Shailaja Kasibhatla
- Joshua Plum
- Rui Li (ORCID: https://orcid.org/0000-0002-5878-6654)
- Shu Xin Zhang (ORCID: https://orcid.org/0000-0003-2543-5943)
- Yanbo Wang (ORCID: https://orcid.org/0000-0002-0787-7361)
- Jun Tang (ORCID: https://orcid.org/0000-0002-9788-8389)
- S. Todd Meyer (ORCID: https://orcid.org/0000-0002-8970-9248)
- Ryan J. Hansen
Institutions
- Pennsylvania State University (US)
- Howard Hughes Medical Institute (US)
- University of California San Diego (US)
- Boundless Bio (United States) (US)
- Stanford Medicine (US)
- Stanford University (US)
Publication Details
- Journal
- Nature
- Published
- 2024-11-06
- DOI
- https://doi.org/10.1038/s41586-024-07802-5
- Citations
- 72
- Primary Topic
- Cancer Genomics and Diagnostics
- Type
- article
- Field-Weighted Citation Impact
- 20.53