Drugging the Cancers Addicted to DNA Repair

Jac A. Nickoloff, Dennie Jones, Suk Hee Lee, Elizabeth A. Williamson, Robert Hromas

Research output: Contribution to journalReview article

39 Scopus citations

Abstract

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

Original languageEnglish (US)
Article numberdjx059
JournalJournal of the National Cancer Institute
Volume109
Issue number11
DOIs
StatePublished - Nov 1 2017

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Nickoloff, J. A., Jones, D., Lee, S. H., Williamson, E. A., & Hromas, R. (2017). Drugging the Cancers Addicted to DNA Repair. Journal of the National Cancer Institute, 109(11), [djx059]. https://doi.org/10.1093/jnci/djx059