Enhancing transcription–replication conflict targets ecDNA-positive cancers

Jun Tang, Natasha E. Weiser, Guiping Wang, Sudhir Chowdhry, Ellis J. Curtis, Yanding Zhao, Ivy Tsz-Lo Wong, Georgi K. Marinov, Rui Li, Philip Hanoian, Edison Tse, Salvador Garcia Mojica, Ryan Hansen, Joshua Plum, Auzon Steffy, Snezana Milutinovic, S. Todd Meyer, Jens Luebeck, Yanbo Wang, Shu Zhang, Nicolas Altemose, Christina Curtis, William J. Greenleaf, Vineet Bafna, Stephen J. Benkovic, Anthony B. Pinkerton, Shailaja Kasibhatla, Christian A. Hassig (), Paul S. Mischel () and Howard Y. Chang ()
Additional contact information
Jun Tang: Stanford University School of Medicine
Natasha E. Weiser: Stanford University School of Medicine
Guiping Wang: Stanford University
Sudhir Chowdhry: Boundless Bio
Ellis J. Curtis: Stanford University School of Medicine
Yanding Zhao: Stanford University
Ivy Tsz-Lo Wong: Stanford University School of Medicine
Georgi K. Marinov: Stanford University School of Medicine
Rui Li: Stanford University
Philip Hanoian: Pennsylvania State University
Edison Tse: Boundless Bio
Salvador Garcia Mojica: Boundless Bio
Ryan Hansen: Boundless Bio
Joshua Plum: Boundless Bio
Auzon Steffy: Boundless Bio
Snezana Milutinovic: Boundless Bio
S. Todd Meyer: Boundless Bio
Jens Luebeck: University of California
Yanbo Wang: Stanford University School of Medicine
Shu Zhang: Stanford University School of Medicine
Nicolas Altemose: Stanford University School of Medicine
Christina Curtis: Stanford University School of Medicine
William J. Greenleaf: Stanford University School of Medicine
Vineet Bafna: University of California
Stephen J. Benkovic: Pennsylvania State University
Anthony B. Pinkerton: Boundless Bio
Shailaja Kasibhatla: Boundless Bio
Christian A. Hassig: Boundless Bio
Paul S. Mischel: Stanford University School of Medicine
Howard Y. Chang: Stanford University

Nature, 2024, vol. 635, issue 8037, 210-218

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41586-024-07802-5

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