About 10,000: it is the number of DNA lesions that every cell in our body undergoes per day. Such a number can be scary at first glance. One almost wonders how cells survive - indeed, how we survive - if our DNA is damaged to this extent on a daily basis.
Repairing the damage is fundamental because DNA contains the instructions for cells to function correctly. If these damages are not repaired, they can result in cell senescence, cell death, and the development of tumours. Fortunately, our cells possess highly efficient repair systems that allow most damage to be corrected before it leads to permanent mutations or cell death.
DNA repair is important, and not just to prevent tumours
Intuitively, one can imagine that researchers study DNA repair mechanisms to prevent cells from accumulating unrepaired damage and thus prevent mutations and carcinogenesis. While this is an important focus, another significant aspect is the potential to exploit flaws in the DNA repair systems of tumour cells to develop targeted therapies. This approach is based on the concept of synthetic lethality, a genetic principle that has paved the way for innovative anti-tumour treatments. This concept is based on the principle that if a cell has two alternative mechanisms available to repair DNA damage, it can survive even if one of the mechanisms is not functioning. Still, the loss of both mechanisms will result in the inability to repair the damage and cell death. To illustrate the concept, let us use a simple analogy. Imagine we need to travel from Bellinzona to Locarno, and we have two options: taking the train or driving a car. If there is a disruption of the railway, we can still reach our destination by car. However, if the road is closed and we cannot drive, our journey will come to a halt. This situation reflects the idea of synthetic lethality. Healthy cells typically use alternative mechanisms to repair DNA damage. However, in some cancer cells, one of these "pathways" can be interrupted, so the cells have to rely on the other mechanism to repair the damage. In a therapeutic setting, a drug can be used to block the alternative repair mechanism (in the previous example, the car journey). In that case, the cancer cells will no longer have any "viable routes" available, and their journey will end.
Synthetic lethality: an opportunity to develop targeted therapies
Synthetic lethality allows the development of targeted therapies that selectively attack tumour cells with defects in DNA repair proteins, reducing the side effects associated with traditional indiscriminate chemotherapy or radiotherapy. The best example of this novel strategy is the use of PARP (poly-ADP-ribose polymerase) enzyme inhibitors for treating tumours with defects in the BRCA1 and BRCA2 genes. Mutations in the BRCA1 and BRCA2 genes are linked to a significantly increased risk of developing various types of cancer, particularly breast and ovarian. Women who carry a BRCA1 mutation have an estimated lifetime risk of developing breast cancer between 50% and 80% and a risk of developing ovarian cancer between 40% and 50%. For those with BRCA2 mutations, the risk for breast cancer ranges from 45% to 70%, while the risk for ovarian cancer falls between 10% and 20%. Additionally, mutations in both BRCA1 and BRCA2 double the risk of developing pancreatic cancer in both men and women, and they are also associated with an increased risk of prostate and stomach cancer. Mutations in the BRCA1 and BRCA2 genes can be hereditary and can be transmitted to children with a high likelihood. Therefore, finding effective therapies for cancers associated with these mutations is crucial.
A success story
The BRCA genes are fundamental for homologous recombination repair, a high-fidelity process that allows the repair of DNA double-strand breaks. When these genes are mutated, homologous recombination is compromised, and the cells can no longer correct the damage using this mechanism but instead become dependent on other repair pathways, such as that mediated by the PARP enzyme, which becomes essential for the survival of the cell. PARP can be blocked through the use of specific drugs such as Olaparib, Rucaparib and Niraparib, and this prevents the repair of DNA breaks, leading to their accumulation and, therefore, to the death of the tumour cell that no longer has the tools to repair the damage. The clinical application of this approach marks a significant advancement in precision medicine. PARP inhibitors are highly effective drugs that can be utilised at low concentrations and act selectively, primarily targeting tumour cells. This selectivity helps to minimise side effects on normal cells.
Healthy cells in the tissues surrounding the tumour that do not have mutations in the BRCA genes possess alternative repair mechanisms, making them less sensitive these specific treatments. This characteristic explains the advantage of targeted therapy, which can effectively reduce tumour proliferation and enhance patient prognosis without major side effects. To give some examples, in a 2017 study, the PARP inhibitor Olaparib was shown to be effective in reducing the risk of breast cancer progression and death by 42% (Olympia Study, The New England Journal of Medicine, 2017). In 2018, another study showed that the use of maintenance therapy with Olaparib in women with ovarian cancer resulted in a 70% lower risk of disease progression or death compared to placebo (The New England Journal of Medicine, Moore and DiSilvestro Groups, 2018). In recent years, with the rapid development of biotechnology, in addition to PARP inhibitors, many drugs designed and developed based on the concept of synthetic lethality have entered clinical trials and will hopefully pave the way for further possibilities in targeted cancer therapies. For example, a promising emerging possibility is to treat some types of colon cancer with inhibitors targeting the WRN protein.
Basic research is the first step in conquering disease
The success of PARP inhibitors highlights the critical role of basic research in developing new drug therapies. This research helps us understand the biological mechanisms behind diseases and identify new therapeutic targets. Without cellular biology, genetics, and biochemistry, we would be unable to create innovative drugs and implement targeted treatment strategies. Therefore, investing in basic research broadens scientific knowledge and is essential for translating discoveries into clinical applications that enhance human health. In the laboratory at the Institute for Research in Biomedicine in Bellinzona, we study DNA repair mechanisms, and we are particularly interested in understanding how BRCA1 and BRCA2 proteins work and how their defects lead to disease.
