The University of Geneva (UNIGE) research team, in collaboration with FoRx Therapeutics based in Basel, has unveiled the mechanism of action behind PARP inhibitors, particularly utilised in treating breast and ovarian cancer among individuals carrying the BRCA gene mutation.
These inhibitors disrupt the engagement of PARP proteins in two distinct functions, safeguarding healthy cells while sustaining their detrimental impact on cancer cells.
Despite the constant DNA damage from thousands of lesions daily, our cell's genome remains stable due to an efficient repair system. Key genes like BRCA1 and BRCA2, crucial for repairing DNA double helix breaks, play a pivotal role. Mutations in these genes (found in about 2 out of every 1,000 women) hinder DNA repair, significantly elevating the risk of breast or ovarian cancer (or prostate cancer in men).
PARP inhibitors have been used to treat this type of cancer for around 15 years. PARP proteins can detect breaks or abnormal structures in the DNA double helix. PARPs then temporarily stick to the DNA, synthesising a chain of sugars which acts as an alarm signal to recruit the proteins involved in DNA repair. Treatments based on PARP inhibitors block these activities and trap the PARP protein in the DNA. There is then no alarm signal to trigger DNA repair.
This treatment targets fast-growing cells like cancer cells, which accumulate mutations rapidly without sufficient time for repair, leading to their demise. However, our bodies also harbor healthy fast-growing cells, such as hematopoietic cells responsible for producing red and white blood cells. Unfortunately, these cells are also significantly affected as collateral damage by anti-PARP treatments.
