Abstract
Simple SummaryGenomic instability is recognized as a driving force in most cancers as well as in the haematological cancer multiple myeloma and remains among the leading cause of drug resistance. Several evidences suggest that replicative stress exerts a fundamental role in fuelling genomic instability. Notably, cancer cells rely on a single protein, ATR, to cope with the ensuing DNA damage. In this perspective, we provide an overview depicting how replicative stress represents an Achilles heel for multiple myeloma, which could be therapeutically exploited either alone or in combinatorial regimens to preferentially ablate tumor cells. 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 per se 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.
Highlights
Multiple Myeloma (MM) is a hematological malignancy characterized by the accumulation of malignant plasma cells in the bone marrow and, during the progression of the disease, in the peripheral blood and other extramedullary sites
MYC may promote cell cycle progression and replicative stress through indirect mechanisms, by regulating the expression of genes involved in cellular proliferation [43] and DNA replication, including the majority of genes involved in the nucleotide biosynthesis pathway [44]
Accumulation of reactive oxygen species (ROS) leads to the formation of 8-oxoguanine, and the resulting oxidative DNA damage causes the replication fork to stall at lesions, promoting replicative stress in cancer cells [42,46,47]
Summary
Multiple Myeloma (MM) is a hematological malignancy characterized by the accumulation of malignant plasma cells in the bone marrow and, during the progression of the disease, in the peripheral blood and other extramedullary sites. Molecular profiling technologies, including fluorescence in situ hybridization (FISH), microarray gene expression profiling (GEP), array comparative genomic hybridization (CGH), single-nucleotide polymorphism (SNP) arrays, and, recently, generation sequencing (NGS), have brought a fairly comprehensive view on the genomic landscape of MM [5] This knowledge has led to the identification of several molecular drivers triggering MM initiation and progression but has, disappointingly, failed to provide effective therapeutic targets or even biomarkers that could be used to dictate treatment strategies [5]. 3 (IKZF1 and IKZF3), and interfere with angiogenesis [9,10]; and most recently, of anti-CD-38 monoclonal antibodies [11,12,13,14], which have led to an important improvement in the survival of MM patients Despite this impressive evolution of treatment regimens, MM remains an incurable disease [15], warranting new therapeutic strategies. We will attempt to provide the groundwork for supporting the notion that blood cancers, in particular, MM, are endowed with rampant genomic instability rooted in replicative stress, which could be exploited for therapeutic reasons
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