美国耶鲁大学医学院Faye A. Rogers小组取得一项新突破。他们发现直接靶向扩增基因位点有利于促凋亡抗癌治疗。相关论文于2021年10月28日发表于国际学术期刊《自然-生物技术》杂志。
在本研究中，研究人员介绍了一种靶向癌症细胞基因扩增的新治疗策略，其利用三链形成的寡核苷酸(TFO)激活DNA损伤反应来诱导肿瘤细胞凋亡，而没有基因扩增的细胞则具有较低水平的DNA损伤。针对HER2扩增诱导的癌症，研究发现靶向HER2的TFO通过HER2细胞功能非依赖性的方式造成HER2阳性癌细胞或人类肿瘤异种移植物中拷贝数依赖的DNA双链断裂(DSB)和激活P53非依赖性细胞凋亡。
已证明该策略的体内功效可与当前精准药物相媲美，并为HER2阳性乳腺癌和卵巢癌模型中耐药性问题的解决提供了可行的替代方案。该发现为扩增基因组位点诱导肿瘤的治疗提供了新的方案。
据悉，基因扩增促进许多癌症的发生。已经研发出许多药物来抑制扩增驱动基因的蛋白质产物，但它们的临床疗效往往因耐药性而大打折扣。
附：英文原文
Title: Direct targeting of amplified gene loci for proapoptotic anticancer therapy
Author: Kaushik Tiwari, Meetu, Colon-Rios, Daniel A., Tumu, Hemanta C. Rao, Liu, Yanfeng, Quijano, Elias, Krysztofiak, Adam, Chan, Cynthia, Song, Eric, Braddock, Demetrios T., Suh, Hee-Won, Saltzman, W. Mark, Rogers, Faye A.
Issue&Volume: 2021-10-28
Abstract: Gene amplification drives oncogenesis in a broad spectrum of cancers. A number of drugs have been developed to inhibit the protein products of amplified driver genes, but their clinical efficacy is often hampered by drug resistance. Here, we introduce a therapeutic strategy for targeting cancer-associated gene amplifications by activating the DNA damage response with triplex-forming oligonucleotides (TFOs), which drive the induction of apoptosis in tumors, whereas cells without amplifications process lower levels of DNA damage. Focusing on cancers driven by HER2 amplification, we find that TFOs targeting HER2 induce copy number-dependent DNA double-strand breaks (DSBs) and activate p53-independent apoptosis in HER2-positive cancer cells and human tumor xenografts via a mechanism that is independent of HER2 cellular function. This strategy has demonstrated in vivo efficacy comparable to that of current precision medicines and provided a feasible alternative to combat drug resistance in HER2-positive breast and ovarian cancer models. These findings offer a general strategy for targeting tumors with amplified genomic loci. Amplified loci in cancer genomes are directly targeted with triplex-forming oligonucleotides.
DOI: 10.1038/s41587-021-01057-5
Source: https://www.nature.com/articles/s41587-021-01057-5
Nature Biotechnology：《自然—生物技术》，创刊于1996年。隶属于施普林格·自然出版集团，最新IF：68.164
官方网址：https://www.nature.com/nbt/
投稿链接：https://mts-nbt.nature.com/cgi-bin/main.plex
本期文章：《自然—生物技术》：Online/在线发表
