美国斯坦福大学Howard Y. Chang等合作发现，增强转录-复制冲突可以有效地靶向具有ecDNA阳性的癌症。该项研究成果发表在2024年11月6日出版的《自然》上。

研究人员表示，染色体外DNA（ecDNA）是癌症患者面临的一个重大挑战。ecDNA通过促进大量癌基因转录和快速基因组进化，使肿瘤治疗产生耐药性，从而导致患者生存不良。目前，还没有针对ecDNA的治疗方法。

研究表明，增强转录-复制冲突能够靶向消除具有ecDNA阳性的癌症。对ecDNA转录的逐步分析表明，与染色体位点相比，普遍存在RNA转录和相关单链DNA，导致过度的转录-复制冲突和复制应激。在含有ecDNA的肿瘤中，无论癌症类型或致癌基因，核苷酸结合在ecDNA上的速度明显较慢，复制压力明显较高。

pRPA2-S33是一种结合单链DNA的DNA损伤修复因子，以转录依赖的方式在ecDNA上显示出升高的定位，同时增加DNA双链断裂，并激活S期检查点激酶CHK1。遗传或药理学抑制CHK1在含有ecDNA的肿瘤中，引起广泛和优先的肿瘤细胞死亡。

该研究推出了一种高选择性、强效和生物可利用的口服CHK1抑制剂BBI-2779，可优先杀死含有ecDNA的肿瘤细胞。在ecDNA上扩增的含有FGFR2的胃癌模型中，BBI-2779抑制肿瘤生长，并阻止ecDNA介导的对泛FGFR抑制剂infigratinib的获得性耐药，导致小鼠肿瘤有效且持续消退。转录-复制冲突成为了ecDNA定向治疗的靶标，利用过量的合成致死性来治疗癌症。

附：英文原文

Title: Enhancing transcription–replication conflict targets ecDNA-positive cancers

Author: 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.

Issue&Volume: 2024-11-06

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 survival1,2,3,4,5,6,7. 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.

DOI: 10.1038/s41586-024-07802-5

Source: https://www.nature.com/articles/s41586-024-07802-5