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Every day the DNA in our cells is damaged thousands of times by natural causes and external factors. If not corrected, this DNA damage (mutation) could eventually lead to cancer. The body has developed systems to protect the cells from DNA damage, called the DNA Damage Response or DDR.

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A faulty DNA Damage Response system can lead to cancer because it allows mutations that promote uncontrolled cell growth to go unrepaired.  Cancer cells with a DNA Damage Response deficiency are heavily reliant on remaining ‘back up’ DNA Damage Response systems.

DNA Damage Response Inhibition is a type of cancer treatment that exploits these defects by blocking the remaining response systems cancer cells are relying on to survive, which in turn causes them to die. Healthy cells are not vulnerable to this type of treatment.

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Poly (ADP-ribose) polymerase (PARP)

The Poly (ADP-ribose) polymerase 1 protein is known to play a major role in the repair of DNA single strand breaks. When PARP 1 is inhibited this can lead to the formation of DNA double strand breaks that have to be repaired through a pathway known as homologous recombination repair (HRR). Cancer cells that have deficiencies in HRR are unable to accurately repair such DNA damage when PARP 1 is inhibited. The cancer cell then accumulates DNA errors resulting in genomic instability to an extent that it can no longer survive. Normal cells, because they retain their HRR capability, are not affected in this way.

PARP inhibitors work by preventing cancer cells from repairing themselves which results in cell death. PARP inhibitors can be used to treat some patients with breast, ovary, pancreatic, and prostate cancer. 

Other targets in DDR

  • WEE1: WEE1 protein kinase activity regulates cell cycle progression allowing cancer cells time to repair DNA damage. WEE1 is over expressed in many breast, lung and colon cancers, and has a key role in the RSR, suggesting cancer cells rely heavily on this mechanism.
  • ATR: ATR is a key protein kinase responsible for regulating the RSR. It plays multiple roles in this respect, including providing a cell cycle checkpoint role as well as facilitating DNA double strand break repair.
  • ATM: ATM is a protein kinase involved in activating DNA damage cell cycle checkpoint and coordinating the repair of DNA double-strand breaks through different pathways, including HRR and non-homologous end joining (NHEJ). If ATM is inhibited in combination with DNA damaging agents (e.g. radiation and chemotherapy), this can lead to an increase in DNA double strand breaks above the threshold tolerated by cancer cells.
  • Aurora B: Aurora B protein kinase assists in DNA chromosome alignment during cell division. Its inhibition causes either unequal splitting of the chromosomes between the daughter cells or failure of the cell to divide, leading to cell death. Aurora B kinase is known to be over-expressed in liver, colon, breast, renal, lung and thyroid cancers. Inhibition of Aurora B kinase has the potential to increase mitotic stress and therefore be combined with other DDR agents.
  • DNA-PK: DNA dependent protein kinase (DNA-PK) is critical in repairing DNA double strand breaks through the NHEJ pathway. DNA-PK has also been linked to the RSR. Opportunities exist for combining an inhibitor of DNA-PK with DNA double strand break inducing agents, as well as other DDR agents that target the RSR. 
General PMF Newsletter 490