Some anticancer drugs target healthy cells in addition to malignant cells. If their effect on the latter is excessively powerful their use may be restricted. The mechanism of action of PARP inhibitors, which are used to treat breast and ovarian cancer specifically in individuals with BRCA gene mutations, has been determined by a team from the University of Geneva (UNIGE) in collaboration with Basel-based FoRx Therapeutics. Has gone. These inhibitors prevent the PARP protein from engaging in two different functions. Healthy cells are protected while harmful effects on cancer cells are maintained by inhibiting one of them.
This research published in the journal Nature will increase the effectiveness of these treatments. (Also read | What is the breast cancer risk calculator recommended by Olivia Munn?,
Despite the thousands of lesions that damage our DNA every day, the genome of our cells is particularly stable thanks to a highly efficient repair system. Among the genes coding for repair proteins are BRCA1 and BRCA2 (for breast cancer 1 and 2), which are specifically involved in DNA double helix breaks. The presence of mutations in these genes (in about 2 out of every 1,000 women) can result in damaged DNA not being repaired, and can significantly increase the risk of developing breast or ovarian cancer (or prostate cancer in men).
PARP inhibitors have been used to treat this type of cancer for about 15 years. PARP proteins can detect breaks or abnormal structures in the DNA double helix. PARPs then temporarily stick to the DNA, synthesizing a chain of sugars that acts as an alarm signal to recruit proteins involved in DNA repair. Treatments based on PARP inhibitors block these activities and trap PARP proteins on DNA. Then there is no alarm signal to initiate DNA repair.
This treatment proves to be toxic for fast-growing cells like cancer cells, which generate too many mutations without being given time to repair and are thus doomed to die. But our body is also home to fast-growing healthy cells. This is the case, for example, of hematopoietic cells – the source of red and white blood cells – which, as collateral victims, are also largely destroyed by anti-PARP treatments.
The mechanism by which anti-PARP drugs kill cells (cancerous or not) is still poorly understood. The laboratory of Professor Thanos Halazonetis in the Department of Molecular and Cellular Biology at the UNIGE Faculty of Sciences has, in collaboration with Forex Therapeutics, dissected the mechanism of action of PARP inhibitors. The scientists used two classes of PARP inhibitors that similarly block PARP’s enzymatic activity – that is, the synthesis of the sugar chain that acts as an alarm signal – but do not trap PARP on DNA with the same strength. Is. The team observed that both inhibitors kill cancer cells with similar efficiency, but the inhibitors that bind PARP weakly to DNA are much less toxic to healthy cells.
“We found that PARP not only acts as an alarm signal to recruit DNA repair proteins, but it also interferes when different machineries read or copy the same part of the DNA,” Michaelis explains. “Abnormal DNA structures are formed as a result of collisions between DNA molecules,” said Petropoulos, post-doctoral fellow in the Department of Molecular and Cellular Biology at UNIGE’s Faculty of Science and first author of the study.
When using anti-PARP treatment, this warning signal is not triggered to prevent a collision. These collisions between the machinery will lead to DNA lesions that cannot be repaired in cancer cells, because they lack the BRCA repair protein. The second activity of PARP therapy, which results in tight binding of PARPs to DNA, aka trapping, also causes DNA damage that requires repair by cells. But this repair is not mediated by the BRCA repair proteins and as a result, both normal and cancer cells are destroyed.
”So we found that inhibition of enzyme activity is sufficient to kill cancer cells, whereas trapping – when PARP is strongly bound to DNA – also kills normal cells, and is therefore responsible for the toxicity of these drugs. This knowledge will make it possible to develop safer PARP inhibitors that block the enzymatic activity of PARP without trapping it on DNA,” summarizes Thanos Halazonetis, head of the study.
