Botrugno Oronza A, Tonon Giovanni
Functional Genomics of Cancer Unit, Experimental Oncology Division, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy.
Cancers (Basel). 2021 Dec 22;14(1):25. doi: 10.3390/cancers14010025.
Multiple Myeloma (MM) is a genetically complex and heterogeneous hematological cancer that remains incurable despite the introduction of novel therapies in the clinic. Sadly, despite efforts spanning several decades, genomic analysis has failed to identify shared genetic aberrations that could be targeted in this disease. Seeking alternative strategies, various efforts have attempted to target and exploit non-oncogene addictions of MM cells, including, for example, proteasome inhibitors. The surprising finding that MM cells present rampant genomic instability has ignited concerted efforts to understand its origin and exploit it for therapeutic purposes. A credible hypothesis, supported by several lines of evidence, suggests that at the root of this phenotype there is intense replicative stress. Here, we review the current understanding of the role of replicative stress in eliciting genomic instability in MM and how MM cells rely on a single protein, Ataxia Telangiectasia-mutated and Rad3-related protein, ATR, to control and survive the ensuing, potentially fatal DNA damage. From this perspective, replicative stress represents not only an opportunity for MM cells to increase their evolutionary pool by increasing their genomic heterogeneity, but also a vulnerability that could be leveraged for therapeutic purposes to selectively target MM tumor cells.
多发性骨髓瘤（MM）是一种基因复杂且异质性的血液系统癌症，尽管临床上引入了新的治疗方法，但仍无法治愈。遗憾的是，尽管经过了数十年的努力，基因组分析仍未能确定该疾病中可作为靶点的共同基因畸变。为寻求替代策略，人们进行了各种尝试，试图针对并利用MM细胞的非癌基因成瘾性，例如蛋白酶体抑制剂。MM细胞呈现出猖獗的基因组不稳定性这一惊人发现，引发了人们为了解其起源并将其用于治疗目的而做出的协同努力。有几条证据支持的一个可信假设表明，这种表型的根源是强烈的复制应激。在此，我们综述了目前对复制应激在引发MM基因组不稳定性中的作用的理解，以及MM细胞如何依赖单一蛋白质——共济失调毛细血管扩张突变和Rad3相关蛋白（ATR）来控制并在随之而来的潜在致命DNA损伤中存活。从这个角度来看，复制应激不仅为MM细胞通过增加其基因组异质性来扩大其进化库提供了机会，也是一个可被利用用于治疗目的、选择性靶向MM肿瘤细胞的弱点。
