DDR in Cancer

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Replication stress and cancer

Replication stress is a source of genomic instability that occurs when the genome is exposed to various stresses, typically during DNA replication[1, 2]. Increased levels of replication stress may occur through, for example, overexpression of oncogenes such as cyclin E, c-MYC or K-Ras [3].

Replication stress is characterised by generation of aberrant replication fork structures containing single-stranded DNA and can manifest in a number of forms (listed 1 to 10 in the figure below)[3, 4]. These stresses slow down or stall DNA polymerase progression and result in DNA polymerisation being uncoupled from the helicase that is unwinding the DNA. The corresponding unrepaired DNA damage that results from such replication stress can result in premature mitosis, and increased mutagenesis, and ultimately lead to the increased genome instability seen in cancer cells [2, 4].

Figure 5: Replication stress-caused DNA damage that can occur during DNA replication

Figure 5: Replication stress-caused DNA damage that can occur during DNA replication

Exploiting replication stress as a therapeutic approach

Excessive replication stress in cancer cells can lead to unsustainable levels of damage, and result in cancer cell death. This has become a target for development of new cancer therapies that could exploit this, and use the increased proliferation rate seen in cancer cells versus normal healthy cells to specifically target fast-growing cancers. This circumvents one of the key limitations of many DNA-damaging cancer therapies, which is their inability to selectively target cancer cells that in turn leads to toxic effects on healthy cells and unwanted adverse effects for patients.

Targeting DNA damage repair mechanisms focuses anticancer therapy specifically on cancer cells that already possess high levels of DNA damage. In this sense, a range of new anticancer therapies that target the DDR pathways are being developed to exploit replication stress in cancer cells [2-4].

Information on selecting patients for treatment with agents targeting DDR and mechanisms of resistance can be found by clicking on the links below:

Click on the links below the references to find out more about targeting DDR in cancer.

References

  1. Gourley C, Balmana J, Ledermann JA et al. Moving from PARP Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019; doi: 10.1200/JCO.1218.02050. [Epub ahead of print].
  2. Jeggo PA, Pearl LH, Carr AM. DNA repair, genome stability and cancer: a historical perspective. Nat Rev Cancer 2016; 16: 35-42.
  3. O'Connor MJ. Targeting the DNA Damage Response in Cancer. Mol Cell 2015; 60: 547-560.
  4. Dobbelstein M, Sorensen CS. Exploiting replicative stress to treat cancer. Nat Rev Drug Discov 2015; 14: 405-423.