Trends in Cancer
Volume 2, Issue 11, November 2016, Pages 646-656
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Opinion
The ‘Pushmi-Pullyu’ of DNA REPAIR: Clinical Synthetic Lethality

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DNA repair inhibitors interrupt normal DNA repair in an injurious fashion.

DNA repair inhibitors coupled with agents damaging DNA or altering the temporal kinetics for DNA repair have shown preliminary promise upon which to build for clinical synthetic lethality.

This process, clinical synthetic lethality, can be obtained by combining targeted agents to optimize malignant cell injury and subsequent cell death.

Maintenance of genomic integrity is critical for adaptive survival in the face of endogenous and exogenous environmental stress. The loss of stability and fidelity in the genome caused by cancer and cancer treatment provides therapeutic opportunities to leverage the critical balance between DNA injury and repair. Blocking repair and pushing damaged DNA through the cell cycle using therapeutic inhibitors exemplify the ‘pushmi-pullyu’ effect of disrupted DNA repair. DNA repair inhibitors (DNARi) can be separated into five biofunctional categories: sensors, mediators, transducers, effectors, and collaborators that recognize DNA damage, propagate injury DNA messages, regulate cell cycle checkpoints, and alter the microenvironment. The result is cancer therapeutics that takes advantage of clinical synthetic lethality, resulting in selective tumor cell kill. Here, we review recent considerations related to DNA repair and new DNARi agents and organize those findings to address future directions and clinical opportunities.

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.

References (55)

  • A. Tutt

    Oral poly(ADP-ribose) polymerase inhibitor olaparib in patients with BRCA1 or BRCA2 mutations and advanced breast cancer: a proof-of-concept trial

    Lancet

    (2010)
  • W.G. Kaelin

    The concept of synthetic lethality in the context of anticancer therapy

    Nat. Rev. Cancer

    (2005)
  • D.P. McLornan

    Applying synthetic lethality for the selective targeting of cancer

    N. Engl. J. Med.

    (2014)
  • T. Lindahl et al.

    Quality control by DNA repair

    Science

    (1999)
  • H. Lofting

    The Story of Doctor Dolittle: Being the History of His Peculiar Life at Home and Astonishing Adventures in Foreign Parts Never Before Printed

    (1920)
  • E.J. Brown et al.

    ATR disruption leads to chromosomal fragmentation and early embryonic lethality

    Genes Dev.

    (2000)
  • J.H. Hoeijmakers

    Genome maintenance mechanisms for preventing cancer

    Nature

    (2001)
  • A.B. Williams et al.

    p53 in the DNA-damage-repair process

    Cold Spring Harb. Perspect. Med.

    (2016)
  • Z. Chen

    Human Chk1 expression is dispensable for somatic cell death and critical for sustaining G2 DNA damage checkpoint

    Mol. Cancer Ther.

    (2003)
  • P. Nghiem

    ATR inhibition selectively sensitizes G1 checkpoint-deficient cells to lethal premature chromatin condensation

    Proc. Natl. Acad. Sci. U.S.A.

    (2001)
  • R.D. Wood

    Human DNA repair genes

    Science

    (2001)
  • A. Sancar

    Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints

    Annu. Rev. Biochem.

    (2004)
  • A. Porro

    Editorial: grappling with the multifaceted world of the DNA damage response

    Front. Genet.

    (2016)
  • H.E. Bryant

    Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase

    Nature

    (2005)
  • H. Farmer

    Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy

    Nature

    (2005)
  • S.G. Swisher

    Adenovirus-mediated p53 gene transfer in advanced non-small-cell lung cancer

    J. Natl. Cancer Inst.

    (1999)
  • P.M. Glazer

    Hypoxia and DNA repair

    Yale J. Biol. Med.

    (2013)
  • Cited by (0)

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