Certain medications used to treat cancer can also affect healthy cells along with the cancerous cells. If the impact on healthy cells is too strong, there may be limitations on the use of these medications. A team from the University of Geneva, in collaboration with FoRx Therapeutics based in Basel, has identified the mechanism of action of PARP inhibitors. These inhibitors are specifically used for individuals with the BRCA gene mutation who have breast or ovarian cancer. By preventing the PARP proteins from performing two specific functions, these inhibitors protect healthy cells while still exerting a harmful effect on cancer cells.
The stability of our cell's genome is largely maintained by a robust repair system, with key genes such as BRCA1 and BRCA2 playing crucial roles in repairing DNA double-strand breaks. Mutations in these genes significantly elevate the risk of breast, ovarian, or prostate cancer. Over the past 15 years, PARP inhibitors have been utilized to treat such cancers by interfering with the repair process. These inhibitors work by preventing PARP proteins from signaling DNA repair, ultimately leading to cell death, particularly in rapidly dividing cancer cells. However, these treatments also harm healthy fast-growing cells, like hematopoietic cells responsible for blood cell production, due to their collateral damage.
Despite the efficacy of PARP inhibitors in killing cancer cells, the precise mechanisms behind their action have remained unclear. Professor Thanos Halazonetis's team at UNIGE Faculty of Science, in collaboration with FoRx Therapeutics, delved into this mystery. Their research focused on dissecting how PARP inhibitors function at a molecular level. They observed that while different inhibitors could equally block PARP's enzymatic activity, they varied in their ability to trap PARP on DNA. Interestingly, the inhibitor that weakly bound PARP to DNA proved to be less toxic to healthy cells while maintaining efficacy against cancer cells.
The study revealed a dual role for PARP in DNA repair. Not only does it serve as a signaling molecule to recruit repair proteins, but it also intervenes when abnormal DNA structures arise from collisions between different DNA-processing machineries. By inhibiting PARP activity, the warning signal to prevent such collisions is suppressed, resulting in increased DNA damage, particularly lethal for cancer cells lacking BRCA repair proteins. Additionally, the trapping of PARP on DNA, caused by some inhibitors, exacerbates DNA damage in both cancer and normal cells, leading to their demise.
The findings underscore that inhibiting PARP's enzymatic activity alone is sufficient to kill cancer cells, while trapping PARP on DNA contributes to the toxicity of current drugs. This understanding paves the way for the development of safer PARP inhibitors that selectively block PARP's enzymatic activity without inducing trapping, thus sparing healthy cells while effectively targeting cancer cells.
