Why target the DNA Damage Response to fight cancer?
The therapeutic approach targeting the DNA Damage Response (or DDR) is a relatively new field in oncology. Its importance has been hailed by the scientific community by the awarding of the 2015 Nobel Prize in Chemistry to three researchers for their studies on DNA repair mechanisms. Professor Tomas Lindahl, a joint recipient of this Nobel Prize, chairs the Valerio Therapeutics Scientific Committee. The inhibition of DNA repair mechanisms in tumor cells is today recognized as one of the most promising ways of treating cancer.
It is based on the fact that cancer cells accumulate DNA breaks, either due to their uncontrolled proliferation, or following treatments such as chemo- or radiotherapy. Not being able to replicate with damaged DNA, their survival is highly dependent on the DNA repair mechanisms, which activate a complex cascade of proteins detecting, signaling, and repairing the breaks. When these mechanisms are impaired, the cancer cells are deprived of the ability to repair their DNA, which leads to their death, when they try to replicate with damaged DNA.
The DNA Damage Response (DDR)
DNA damage response is a sophisticated cascade of cellular events that can be summarized, in a very simplified manner, into three stages:
- Detection and identification of the damage with “sensor” proteins such as PARP.
- Signaling with “transducer” proteins such as DNA-PK, ATR, etc. whose role is essential in coordinating the most appropriate response, repair of the DNA break, or destruction of the cell if the damage is too extensive.
- Repair with effector proteins such as RAD, POLQ, etc. which will appropriately repair the DNA molecule (resection, replication, insertion, etc.)