Merdler-Rabinowicz Rona, Dadush Ariel, Patiyal Sumeet, Rajagopal Padma Sheila, Daya Gulzar N, Ben-Aroya Shay, Schäffer Alejandro A, Eisenberg Eli, Ruppin Eytan, Levanon Erez Y
Cancer Data Science Lab, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, United States.
Mina and Everard Goodman Faculty of Life Sciences, Bar-Ilan University, Ramat Gan, 5290002, Israel.
NAR Cancer. 2025 May 6;7(2):zcaf016. doi: 10.1093/narcan/zcaf016. eCollection 2025 Jun.
Adenosine deaminases acting on RNA (ADAR) enzymes constitute a natural cellular mechanism that induces A-to-I(G) editing, introducing genetic changes at the RNA level. Recently, interest in the endogenous-ADAR editor has emerged for correcting genetic mutations, consisting of a programmed oligonucleotide that attracts the native ADAR, thereby offering opportunities for medical therapy. Here, we systematically chart the scope of cancer mutations that endogenous-ADAR can correct. First, analyzing germline single nucleotide variants in cancer predisposition genes, we find that endogenous-ADAR can revert a fifth of them, reducing the risk of cancer development later in life. Second, examining somatic mutations across various cancer types, we find that it has the potential to correct at least one driver mutation in over a third of the samples, suggesting a promising future treatment strategy. We also highlight key driver mutations that are amenable to endogenous-ADAR, and are thus of special clinical interest. As using endogenous-ADAR entails delivering relatively small payloads, the prospects of delivering endogenous-ADAR to various cancers seem promising. We expect that the large scope of correctable mutations that are systematically charted here for the first time will pave the way for a new era of cancer treatment options.
作用于RNA的腺苷脱氨酶（ADAR）酶构成了一种自然的细胞机制，可诱导A到I（G）编辑，在RNA水平上引入基因变化。最近，人们对内源ADAR编辑器用于纠正基因突变产生了兴趣，该编辑器由一种可编程寡核苷酸组成，可吸引天然ADAR，从而为医学治疗提供了机会。在这里，我们系统地描绘了内源ADAR可以纠正的癌症突变范围。首先，分析癌症易感基因中的种系单核苷酸变体，我们发现内源ADAR可以使其中五分之一的变体恢复正常，降低日后患癌风险。其次，检查各种癌症类型中的体细胞突变，我们发现它有可能在超过三分之一的样本中纠正至少一个驱动突变，这表明了一种有前景的未来治疗策略。我们还强调了适合内源ADAR纠正的关键驱动突变，因此具有特殊的临床意义。由于使用内源ADAR需要传递相对较小的有效载荷，将内源ADAR递送至各种癌症的前景似乎很广阔。我们预计，这里首次系统描绘的可纠正突变的广泛范围将为癌症治疗选择的新时代铺平道路。
