Synthetic lethality in cancer therapy
Synthetic lethality means two defects that are harmless alone but lethal together: blocking a second DNA repair pathway (a route that mends DNA) kills tumour cells that lack the first.
Remember
A drug that blocks the back-up repair pathway kills a tumour that has already lost the first one, while normal cells that keep both pathways survive.
Normal cells have more than one DNA repair pathway, so if one route is lost, another can back it up and the cell survives. Synthetic lethality describes two defects that are harmless on their own but lethal together.
A tumour that has already lost one repair pathway depends on a second, back-up pathway to survive. A drug that blocks that back-up pathway kills the tumour cells. Normal cells, with both pathways intact, can cope, so they are relatively spared.
The best-known example is the PARP inhibitor (a drug that blocks the enzyme poly(ADP-ribose) polymerase, which helps repair single-strand breaks, meaning breaks in one of the two strands of DNA), used in tumours with BRCA1 or BRCA2 mutations. When PARP is blocked, unrepaired single-strand breaks turn into double-strand breaks (a second kind of DNA break) during replication. Normal cells mend these double-strand breaks by a repair pathway called homologous recombination, but BRCA-mutant tumour cells have a defect in homologous recombination and cannot, so they die.
Synthetic lethality is more selective than classic treatment (the well-established approach of causing more DNA damage, as chemotherapy drugs and radiation do). Classic treatment adds more DNA damage to every dividing cell, so it also harms rapidly dividing normal tissue, which causes side effects such as hair loss and nausea. Synthetic lethality usually works only in a specific context or cancer type.
Key facts
- Principle
- two repair defects together kill the cell, though each alone is tolerated.
- Tumour side
- the tumour already lacks one repair pathway and relies on the other.
- Normal cells
- they keep both pathways, so they are relatively spared.
- Example
- PARP inhibitors in tumours with BRCA1 or BRCA2 mutations.
- Contrast with classic treatment
- classic treatment damages every dividing cell, whereas synthetic lethality exploits a weakness found in the tumour.
- Limitation
- the approach usually works only in a specific context or cancer type.
Exam traps
- Oncogene addiction, where a tumour depends on one overactive growth signal that healthy cells do not need, is a different form of dependence from the way a tumour relies on a back-up repair route.
- Immune-mediated killing, in which T cells recognise tumour cells, is the principle behind immunotherapy, not a drug that blocks a repair pathway.
- Synthetic rescue is the opposite result to synthetic lethality, because it means a second change that restores survival after one defect rather than killing the cell.
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