DNA damage and genomic instability are hallmarks of cancer. This makes the disease-causing cells highly sensitive to drugs that target specific DNA repair factors. This is termed synthetic lethality.
The first type of synthetic lethality to be developed is termed loss-of-function synthetic lethality. This type of synthetic lethality is useful in cancers with inactivating mutations in specific DNA repair factors, that render the cancer cell highly dependent on remaining DNA repair. Targeting one of the remaining DNA repair pathways deprives these cells of their capacity to repair damaged DNA, leading to cancer cell death by synthetic lethality.
The second type of synthetic lethality – pioneered by our scientists – is termed gain-of-function synthetic lethality. This type of synthetic lethality is designed to work in cancers that acquire a new genetic activity that does not exist in normal cells; for example, the activation of an oncogene. This new activity creates DNA damage and cellular stress, causing a reliance on specific DNA repair pathways for cancer cell survival. Targeting these critical repair pathways leads to synthetic lethal DNA damage overload caused by the abnormal genetic activity.
To date, the only synthetic lethal therapies in the clinic are the loss-of-function type. Cyteir Therapeutics is developing the next generation of synthetic lethal therapies targeting cancers with specific gain-of-function abnormalities. Our current lead program targets RAD51 to induce synthetic lethality in diseases with a gain-of-function in the gene AID (also called AIDCA).
Targeting DNA repair mechanisms is the key to synthetic lethal therapies
- Cancer cells have imbalances in DNA damage and repair caused by gains of DNA damaging processes and losses of DNA repair functions
- Imbalances in DNA damage and repair cause rapid mutation and genomic instability
- Targeting specific repair factors causes DNA damage overload specifically in diseased cells
Cyteir is an innovator in DNA repair and synthetic lethality
- Cyteir’s scientists are leading the development of new gain-of-function synthetic lethal therapies
- We have developed a unique and proprietary platform for the discovery and development of new synthetic lethal drugs
- Cyteir’s scientists discovered the gain-of-function synthetic lethal relationship between AID-RAD51
- We are leaders in the development of small molecules that target RAD51 for treatment of cancer
- We are developing new biomarkers of synthetic lethality, including AID