Enhancing transcription-replication conflict targets ecDNA-positive cancers

• 成果类型: Article
• 署名作者: Tang, Jun; Weiser, Natasha E.; Wang, Guiping; Chowdhry, Sudhir; Curtis, Ellis J.; Zhao, Yanding; Wong, Ivy Tsz-Lo; Marinov, Georgi K.; Li, Rui; Hanoian, Philip; Tse, Edison; Mojica, Salvador Garcia; Hansen, Ryan; Plum, Joshua; Steffy, Auzon; Milutinovic, Snezana; Meyer, S. Todd; Luebeck, Jens; Wang, Yanbo; Zhang, Shu; Altemose, Nicolas; Curtis, Christina; Greenleaf, William J.; Bafna, Vineet; Benkovic, Stephen J.; Pinkerton, Anthony B.; Kasibhatla, Shailaja; Hassig, Christian A.; Mischel, Paul S.; Chang, Howard Y.
• 署名单位: Stanford University; Stanford University; Stanford University; Stanford University; University of California System; University of California San Diego; Stanford University; Pennsylvania Commonwealth System of Higher Education (PCSHE); Pennsylvania State University; Pennsylvania State University - University Park; University of California System; University of California San Diego; Stanford University; Stanford University; Stanford Cancer Institute; Stanford University; Howard Hughes Medical Institute
• 刊物名称: Nature
• ISSN/ISSBN: 0028-6552
• DOI: 10.1038/s41586-024-07802-5
• 发表日期: 2024-11-07
• 关键词: serous ovarian-cancer; extrachromosomal dna; chk1; inhibitor; combination; prexasertib; resistance; initiation; stress

摘要

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. Extrachromosomal DNA makes cancerous tumours resistant to treatment, but this research demonstrates that increasing transcription-replication conflict allows for targeted elimination of cancer cells containing extrachromosomal DNA, and thus sustained tumour regression in mice.