refers to a situation where simultaneous alterations in two different genes result in cell death, but a mutation in either gene alone does not. The word synthetic
is used here for its ancient Greek meaning: the combination of two entities to form something new.
The phenomenon of synthetic lethality was first described by the American geneticist Calvin Bridges in the early 20th century, when he noticed that some combinations of mutations in the model organism Drosophila melanogaster
(the common fruit fly) rendered lethality.
When crossing two fruit flies, certain non-allelic genes were lethal only in combination even though the homozygous parents were perfectly viable. The term "synthetic lethality" was coined two decades later by his colleague Theodore Dobzhansky who observed the same phenomenon in wildtype populations of another fruit fly species, Drosophila pseudoobscura.
Synthetic lethality is a consequence of the tendency of organisms to maintain "backup plans" for all key processes in cells -- to protect phenotypic stability even when unpredictable events occur, such as genetic variations, environmental changes, or random mutations. Nature maintains genetic robustness by means of having parallel redundant pathways and "capacitor" proteins
that camouflage the effects of mutations so that important cellular processes remain unaffected by any individual component. In practical terms, in order to exploit the phenomenon of synthetic lethality one needs to identify these buffering relationships, and understand what happens when they break down. Scientists do this through the identification of gene interactions that function in either the same biochemical processes or pathways that appear to be unrelated.
In the context of oncology drug discovery, the synthetic lethality approach indirectly targets loss-of-function mutations, often in tumor suppressing genes. This approach requires the availability of gene pairs that, when simultaneously inactivated, render death of cancer cells. When such a situation occurs (e.g. in Homologous recombination deficiency [HRD] tumors), the strategy is to then target a second gene, one that compensates for the loss of activity of the dysfunctional gene. The best-known examples in cancer involve the tumor-suppressing BRCA
genes, which play a vital role in repairing DNA damage, and PARP
genes that act on a "back-up" repair pathway. In this case, cancer cells can tolerate breaking down one pathway or the other, but not both at the same time.
Loss-of-function mutations in BRCA1
genes are found in roughly 30-40% of familial breast cancer patients and in up to 80% of hereditary ovarian cancer patients, making the synthetic lethality a principle area for anti-tumor drug discovery with a potentially large group of patients who might benefit from such therapeutics. In fact, the first drug exploiting the synthetic lethality phenomenon, PARP inhibitor for treating patients with mutations in BRCA1/BRCA2
genes, was approved in Europe and the United States back in 2014, and since then, three other approved PARP inhibitors followed.