DNA damage can be categorized into single-strand breaks, double-strand breaks, and replication stress. DNA damage causes changes in the structure of the genetic material and prevents the replication mechanism from functioning and performing properly.

Cancer cells increase the amount of DNA damage, and upregulate repair mechanisms. DDR is a complex signal transduction pathway that recognizes when DNA is damaged and initiates the cellular response to the damage.

One mechanism of DNA damage repair depends on PARP. PARP is a protein that helps damaged cells to repair themselves. PARP enzyme binds tightly to DNA strand breaks and allows repair enzymes to repair the damaged DNA.

PARP inhibitors: First success for synthetic lethality concept. Hugely successful; however, they have issues with resistance and the therapeutic window, which limits their combination options.

Compounds targeting kinases acting as central nodes of the DDR pathway. These molecules have been tested in several clinical studies with mild success. Only a handful are still active in the clinic, and they have not replicated the synthetic lethality seen with PARP inhibitors.

This group comprises non-kinase DDR targets, such as helicases, polymerases and nucleases, which regulate more specific mechanisms, thereby increasing their therapeutic window and their potential use in combination with other drugs.