Trends in Cancer
OpinionThe ‘Pushmi-Pullyu’ of DNA REPAIR: Clinical Synthetic Lethality
Section snippets
The ‘Pushmi-Pullyu’ of DNA Repair
What allows individuals to be so remarkably different, yet so very similar, is their genomic variability. Such variability, encoding brown versus blue eyes, blond versus brown hair, and other traits, occurs from normal selection for genomic variants. The hallmark of our longevity and responsiveness to environmental and other exposures is our genomic stability, plasticity, and genomic vigilance. This stability is the result of ongoing monitoring, recognition, and response to genomic changes,
DNA Damage and Repair Pathways
DNA damage and repair pathways have evolved from the less complex prokaryote and lower eukaryote process into a series of distinct and interactive pathways [14]. These DNA repair pathways are the toggles between cell cycle arrest for either repair or apoptosis, and propagation of damage via its conversion into permanent injury. Pathways have specialized to recognize specific subsets of ssDNA error and repair, such as mismatch repair, limited base errors, and crosslinks 3, 15 (Figure 1).
DNA Repair Inhibition as A Therapeutic Target
DNA repair is one side of the DNA stability seesaw. The possibility of targeting key elements of DNA repair pathways for therapeutic benefit gained traction after the recognition that disruption of the poly(ADP) ribose polymerase (PARP) sensor signal could selectively injure cells deficient in HR due to mutational loss of BRCA1 and BRCA2 function 20, 21. This class of agents, built on the biology of competitive inhibition of NAD, which is necessary for the function of the PARP enzyme, went from
Clinical Synthetic Lethality
Clinical synthetic lethality pushes the concept of synthetic lethality from pairs of Drosophila mutations to treatment paradigms for the cancer clinic. Drugs that cause a loss- or gain-of-function phenotype coupled with cancer-specific genomic events, or drugs that are genotypically injurious can result in tumor cell kill. The context of the therapeutic opportunity is important in optimizing selective antitumor effects. Examples of six opportunities are described wherein a cellular-endogenous
Selection Paradigms to Optimize Clinical Synthetic Lethality
Selection of patients for treatment with DNARi using markers of homologous repair defects has started. At present, only deleterious germline BRCA1/2 mutations are considered predictive, prognostic, and fit-for-purpose when selecting patients for treatment with PARPi. Controversy still surrounds the definition of tumor BRCA1/2 mutation because the requirement for homozygosity has not been clarified. This selective/enrichment biomarker has been validated in clinical trials in patients with breast
Concluding Remarks
Clinical synthetic lethality can be broadly defined as an underlying event often seen in cancer that causes a gain- or loss-of-function phenotype or drug that, when combined with a drug targeted to a mutation or dysfunctional pathway, augments antitumor effects. The dynamic interplay between DNA damage and repair inhibition, ‘pushmi-pullyu’, creates a window of opportunity for therapeutic intervention resulting in more than incremental improvement in clinical outcome (see Outstanding
Acknowledgements
To Kristie Magee and Peter Thielen at Technical Resources International for valuable assistance in the editing, proofreading, and assembly, and the development of the figures that accompany this article, respectively. Thank you.
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