Homing in on genomic instability as a therapeutic target in cancer

Abstract

While genomic instability is a hallmark of cancer, its genetic vulnerabilities remain poorly understood. Identifying strategies that exploit genomic instability to selectively target cancer cells is a central challenge in cancer biology with major implications for anti-cancer drug development.The most common form of genomic instability in cancer is chromosomal instability (CIN), a continuous state of mitotic dysfunction that gives rise to karyotypic abnormalities and aneuploidy. Most human cancers exhibit some degree of CIN with consequences for tumor evolution and prognosis. CIN has been linked to other discrete sources of genomic instability such as whole genome doubling (WGD) 1 and loss-of-function mutations in key tumor suppressor genes leading to dysregulated oncogenic signaling 2 . At the cellular level, CIN precipitates intratumoral heterogeneity and allows tumors to explore greater evolutionary space for fitter subclones that can subsequently expand under selective pressure 3 . CIN also causes the release of genomic DNA into the cytosol which triggers an immune response and activates inflammatory pathways that tumor cells can co-opt to promote metastatic dissemination 4 . These properties have significant clinical ramifications, as CIN is now recognized as a biomarker of poor prognosis across a diverse range of cancer types and both CIN and aneuploidy have also been implicated in multidrug resistance 5 , highlighting the importance of DNA copy number profiling in the clinical setting.CIN is attributed in part to altered dynamics in the mitotic spindle that attaches to chromosomes and orchestrates the accurate separation of genetic material during mitosis. The spindle assembly checkpoint (SAC) safeguards against CIN by delaying the onset of anaphase until chromosomes are properly aligned and attached to the spindle. SAC defects can, therefore, lead to chromosome missegregation errors and aneuploid daughter cells. This phenomenon has been demonstrated in vitro. Treatment with small-molecule inhibitors of the SAC kinase MPS1 can induce CIN in near-diploid cell lines to generate aneuploid cell populations harboring random chromosomal aberrations 6 . Similar effects have been observed in transgenic mouse models with SAC deficiency, where overexpression of core SAC components such as Bub1 or Mad2 yields copy number gains and losses of whole chromosomes and enhanced tumor formation 7,8 . Given the relationship between SAC disruption and CIN, spindle proteins are attractive candidates for therapeutic development in CIN tumors. Nevertheless, therapies that target the underlying mechanisms that lead to CIN have proven elusive. While chemotherapies that target the mitotic spindle are commonly used to treat solid tumors, broad inhibition of spindle function as an anti-cancer therapy is complicated by the potential for toxicity 9,10 .New evidence published recently in Nature Communications suggests that inhibition of a specific spindle protein may decrease cell viability in CIN tumor cells with little or no effect on

Apurinic/apyrimidinic nuclease 1 drives genomic evolution contributing to chemoresistance and tumorigenesis in solid tumor

“…These observations suggest that drivers of genomic instability could serve as promising targets to treat and/or prevent cancer. Consistently, it is now becoming more evident that genomic instability is a promising target in cancer 34,35 . The purpose of this study was to identify genes driving genomic instability in EAC as well as other solid tumors.…”

“…Similarly, it has been demonstrated that a genomic instability-related score calculated based on copy number alterations can predict prognosis in luminal A breast cancer 33 . It is now becoming quite evident that genomic instability is a promising target in cancer 34,35 . Chromosomal instability has been implicated in cancer progression and development of resistance to treatment and seems to associate with poor clinical outcome 13 .…”

Comprehensive Analyses Identify APOBEC3A as a Genomic Instability-Associated Immune Prognostic Biomarker in Ovarian Cancer

“…Apart from the impact of immune component, genomic instability would also play a crucial part in influencing immunotherapy response ( 53 ). Genomic instability was acknowledged as one of the hallmarks of cancer and could be frequently observed in a variety of malignant tumors, which was found to be closely related to tumor resistance and progression ( 23 , 53 ). Additionally, multiple studies have made enormous efforts to discover the relationship between genomic instability and immunological processes, ultimately demonstrating that neoantigens could serve as an intermediary bridge for tumor-specific somatic mutations to induce the activation of T lymphocytes ( 53 , 54 ).…”

“…Accumulating evidence has expounded genomic instability as a hallmark of cancer ( 23 , 24 ). Moreover, genomic instability has also been reported as a crucial prognostic signature, which is strongly related to the tumorigenesis and progression ( 25 , 26 ).…”

Unravelling the tumour genome: The evolutionary and clinical impacts of structural variants in tumourigenesis

“…Further, tumours with ecDNAs may be more resistant to targeted oncogenic therapies due to their inherent plasticity and the significant contribution of ecDNAs to intratumoural heterogeneity [124]. In addition, overall genomic instability itself, rather than the presence of a particular SV, may be exploited as a treatment target [195]. A recent study suggested that drug inhibition against KIF18A, a key protein in the maintenance of spindle dynamics, resulted in antiproliferative effects specifically in tumours with increased chromosomal instability [196].…”