التفاصيل البيبلوغرافية
| العنوان: |
Enhancing transcription–replication conflict targets ecDNA-positive cancers. |
| المؤلفون: |
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 |
| المصدر: |
Nature; Nov2024, Vol. 635 Issue 8037, p210-218, 9p |
| مستخلص: |
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. [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |