Synthetic Lethality
Synthetic lethality is the concept that in the relationship between two genes, loss of one gene function is not lethal to the cell due to reliance on a second gene product, however loss of function of both results in cell death. This allows targeting of cancer cells which already carry an inherent mutation in one gene as they can now be killed through therapeutic inhibition of the other. Normal cells, which carry both normal genes, are spared cell death.
The best examples of this approach are poly(ADP-ribose) polymerase 1 (PARP1) inhibitors in (breast cancer) BRCA-1 or BRCA-2 mutation ovarian and breast cancer. PARP is involved in repair of double-strand DNA breaks and, when inhibited, there is an over-reliance on the homologous recombination DNA repair pathway to maintain cellular integrity. BRCA mutation cancers are deficient in homologous recombination, and so, will be killed by PARP inhibition, whereas, normal cells should be unaffected. The PARP inhibitors iniparib and olaparib are undergoing clinical trials in BRCA-mutation cancers.