Healthy cells have mechanisms, collectively known as the DNA damage response (DDR), to detect and repair DNA damage or induce cell death if the damage cannot be fixed.¹

Many cancers have defects in DDR proteins and pathways that may render cells more susceptible to DNA damage.²

In cancer cells, inhibitors of the DDR have the potential to prevent DNA repair or maximize the DNA damage caused by anticancer therapies, ultimately resulting in cancer cell death. Additionally, in tumors that have acquired mutations in 1 or more DDR pathways, rendering them nonfunctional, inhibition of the remaining DDR pathway(s) could be fatal to cancer cells.^1-4

A plethora of proteins are involved in the DDR, but 4 proteins in particular have been identified as playing important roles across several DDR pathways: ATR, ATM, DNA-PK, and PARP.^1-3,5

Ataxia telangiectasia and Rad3-related (ATR) protein kinase serves as a major regulator of the replication stress response. Replication stress leads to the generation of exposed sections of single-stranded DNA, which activates ATR kinase and leads to cell cycle arrest.¹

Ataxia telangiectasia mutated (ATM) protein kinase is a master regulator of the response to DNA double-strand breaks (DSBs). ATM is activated in response to DNA DSBs and serves to induce cell cycle arrest and promote DNA damage repair.^1,4,6

DNA-dependent protein kinase (DNA-PK) is involved in the repair of DSBs via nonhomologous end joining (NHEJ). This process is required for maintaining the integrity of the genome in healthy cells, but it also contributes to the survival of cancer cells exposed to DSB-inducing therapies.^7,8

Poly [ADP-ribose] polymerase (PARP) plays a crucial role in the DNA damage response pathway by promoting single-stranded DNA repair, NHEJ and homologous recombination repair. PARP is recruited and binds to damaged DNA, which results in the recruitment of downstream DNA repair proteins that promote DNA repair.^2,3