Abstract
Simple SummaryCancer onset and progression lead to a high rate of DNA damage, due to replicative and metabolic stress. To survive in this dangerous condition, cancer cells switch the DNA repair machinery from faithful systems to error-prone pathways, strongly increasing the mutational rate that, in turn, supports the disease progression and drug resistance. Although DNA repair de-regulation boosts genomic instability, it represents, at the same time, a critical cancer vulnerability that can be exploited for synthetic lethality-based therapeutic intervention. We here discuss the role of the error-prone DNA repair, named Alternative Non-Homologous End Joining (Alt-NHEJ), as inducer of genomic instability and as a potential therapeutic target. We portray different strategies to drug Alt-NHEJ and discuss future challenges for selecting patients who could benefit from Alt-NHEJ inhibition, with the aim of precision oncology.Error-prone DNA repair pathways promote genomic instability which leads to the onset of cancer hallmarks by progressive genetic aberrations in tumor cells. The molecular mechanisms which foster this process remain mostly undefined, and breakthrough advancements are eagerly awaited. In this context, the alternative non-homologous end joining (Alt-NHEJ) pathway is considered a leading actor. Indeed, there is experimental evidence that up-regulation of major Alt-NHEJ components, such as LIG3, PolQ, and PARP1, occurs in different tumors, where they are often associated with disease progression and drug resistance. Moreover, the Alt-NHEJ addiction of cancer cells provides a promising target to be exploited by synthetic lethality approaches for the use of DNA damage response (DDR) inhibitors and even as a sensitizer to checkpoint-inhibitors immunotherapy by increasing the mutational load. In this review, we discuss recent findings highlighting the role of Alt-NHEJ as a promoter of genomic instability and, therefore, as new cancer’s Achilles’ heel to be therapeutically exploited in precision oncology.
Highlights
In hepatocellular carcinoma (HCC) the lncRNA lncPARP1, which was significantly up-regulated in HCC patients, directly increased the expression of its target PARP1 acting in cis, triggering genomic instability and disease progression [35]
homologous recombination (HR) or NHEJ deficiency is compensated by Alt-NHEJ hyperactivation, which allows the toleration of DNA damage overload produced by increased error rate. These findings suggest that targeting a backup repair pathway to which cancer cells are addicted could be exploited to selectively kill tumor cells while sparing normal cells, making Alt-NHEJ a promising target for the treatment of DNA damage response (DDR)-deficient cancer cells [64].There are three main strategies to target Alt-NHEJ repair: (1) inhibiting the first step by PARP inhibitors (PARPis), (2) preventing DNA synthesis at gaps targeting
Cancer cells often rely on error-prone DNA repair that allows survival by increasing the mutagenic rate, which in turn promotes genomic instability, disease progression and drug resistance [98,99]
Summary
Cancer is a multi-step disease in which different features, conferring malignant phenotype, are progressively acquired. (2) chromosomal instability (CIN), the most common, characterized by structural or numeric chromosomal aberrations [3]; (3) nucleotide instability (NIN), defined by the presence of base substitutions, deletions, or insertions These mutation prone phenotypes could derive from increased cell sensitivity to exogenous or endogenous mutagens and/or from loss of mechanisms, which normally act as genome guardians, such as p53, driving genetically damaged cells into senescence or apoptosis. In this context, DNA repair machinery defects play a crucial role in fostering genomic instability by promoting accumulation of genetic changes which lead to neoplastic transformation or tumor progression [4]
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