Damage to DNA is a common event – it is estimated that even in normal tissues there are thousands of breaks in the DNA of a single cell each day. The vast majority of these breaks are repaired by specialist mechanisms called DNA damage response pathways. Most, if not all, cancer cells have some defects in one or more of their DNA damage response pathways. This hinders the cell’s ability to repair DNA and therefore damaged DNA accumulates in the cells. This is one of the main ways that cancer cells accrue the mutations and instability that distinguishes them from normal cells.
This damage also renders them unstable and prone to lethal damage. For example, new treatments such as PARP inhibitors exploit DNA damage in a cancer cell, leading to cell death. PARP inhibitors stop a particular mechanism of DNA repair, and when this is prevented, it can be lethal for the cancer cell and yet not toxic for normal cells.
Given the range of pathways involved in repairing DNA, and the range of new drugs being developed to target such defects (such as PARP inhibitors), it is important to identify the specific defects in each patient’s tumour before an effective treatment can be delivered. This project sought to develop new techniques for identifying which DNA damage response pathways do not working properly in specific tumours.