The 2015 Nobel Prize in Chemistry was awarded for work on the mechanisms of DNA repair and their importance in human physiology.
The therapeutic potential of targeting DNA repair, and the synthetic lethality approach, has been validated by the success of three approved DNA repair inhibitors that target poly (ADP ribose) polymerase (PARP).
Each of the estimated 30 trillion cells in the human body experiences sporadic and occasional DNA damage. Humans have evolved efficient DNA repair systems with multiple fail-safe redundancies to ensure the accurate repair of this damaged DNA.
Diseased cells, by contrast, can incur significantly more DNA damage, nearly to the limit of their repair capacity. DNA damage that escapes repair can lead to mutations or unstable chromosomes which, in turn, can exacerbate disease.
By therapeutically targeting DNA repair, diseased cells – but not healthy normal cells – can be pushed past their DNA damage survival limit and will thus self-destruct as a consequence of DNA damage overload.
Synthetic lethality is a phenomenon, first discovered in genetic model systems, in which two genetic dysfunctions – neither of which is detrimental on its own – combine to kill a cell.
The first synthetic lethal interactions discovered were caused by mutations that resulted in loss of activity in pairs of genes. An example of this loss-of-function type of synthetic lethality occurs with BRCA1/2 mutations and the DNA repair factor poly (ADP ribose) polymerase, or PARP. This biology has been the focus of intense pharmaceutical interest, with four different PARP inhibitors approved for use as synthetic lethal therapies in BRCA defective ovarian cancers.
Our scientists have discovered a new type of synthetic lethality, based on genetic gains-of-function. Cancers acquire new genetic features that do not exist in normal, healthy cells or tissues. Many of these genetic gains-of-function – for example, in oncogenes that drive cancer – lead to excessive DNA damage and create excessive stress on the diseased cell. To survive this elevated stress, diseased cells require specific DNA repair systems. Cyteir is developing a new generation of novel synthetic lethal therapies that precisely target the specific DNA repair systems needed for cells to survive these disease-causing gain-of-function events.