Exploiting Synthetic Lethality as an Anti-Cancer Therapy

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Synthetic lethality was first described in fruit flies (Drosophila melanogaster) for situations where two single genetic, loss-of-function events had no effect on viability alone, but when combined resulted in cell death [1]. This concept was originally used to explain the cell death observed in BRCA-deficient cells when PARP was inhibited [2, 3]. However, this is now considered a misconception as loss-of-function mutations in both BRCA and PARP1 genes generally does not result in lethality. It is now apparent that it is the trapping of PARP1 on DNA following its inhibition, which confers lethality to HRD [4, 5].

Pre-clinical studies have shown that PARP inhibitor resistance in BRCA-mutated tumours can arise by downregulating PARP1 thereby removing the ability to trap PARP on DNA [6].

However, the concept of synthetic lethality is still relevant to targeting DDR pathways as therapeutic targets [7-9]. The figure below shows the outcomes that might be expected when targeting individual DDR proteins compared with exploiting synthetic lethal DDR relationships in cells with DNA damage [4].

A: When there are no defective DNA repair pathways, the cell remains alive.

B, C: When only one DNA repair pathway is defective, cells can usually repair DNA damage by switching to an alternative repair mechanism.

D: When one pathway is defective and the backup repair mechanism is also targeted by pharmacological intervention, neither pathway is functional, and the cancer cell is unable to survive.

Figure 7: Concept of synthetic lethality[4]

Figure 7: Concept of synthetic lethality

Adapted from Gourley, et al., J Clin Oncol 2019

Click here  to find out more about identifying synthetic lethal targets for therapy.

References

  1. Lucchesi JC. Synthetic lethality and semi-lethality among functionally related mutants of Drosophila melanfgaster. Genetics 1968; 59: 37-44.
  2. Farmer H, McCabe N, Lord CJ et al. Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature 2005; 434: 917-921.
  3. Bryant HE, Schultz N, Thomas HD et al. Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature 2005; 434: 913-917.
  4. 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].
  5. Murai J, Huang SY, Das BB et al. Trapping of PARP1 and PARP2 by Clinical PARP Inhibitors. Cancer Res 2012; 72: 5588-5599.
  6. Pettitt SJ, Krastev DB, Brandsma I et al. Genome-wide and high-density CRISPR-Cas9 screens identify point mutations in PARP1 causing PARP inhibitor resistance. Nat Commun 2018; 9: 1849.
  7. Ashworth A. A synthetic lethal therapeutic approach: poly(ADP) ribose polymerase inhibitors for the treatment of cancers deficient in DNA double-strand break repair. J Clin Oncol 2008; 26: 3785-3790.
  8. Lord CJ, Ashworth A. PARP inhibitors: Synthetic lethality in the clinic. Science 2017; 355: 1152-1158.
  9. Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 2012; 12: 801-817.
Last update: 25 July 2019