How tumours bypass treatment with olaparib, a new drug for a hereditary form of ovarian cancer
4 April 2015
As part of international cooperation with the Dutch and other scientific teams, scientists from the Institute of Molecular and Translational Medicine (IMTM) of the Medical Faculty of Palacky University and the University Hospital in Olomouc have described a new mechanism by which tumour cells can acquire resistance to treatment. They published the results of their new discovery, which is considered to be a significant achievement throughout the scientific world, and not only in the Czech Republic, in Nature, one of the most prestigious international journals.
Their work focused on tumours with mutations in the BRCA1 gene, occurring mainly on the basis of genetic predisposition to a hereditary form of breast and ovarian cancer. This gene, recently also popularised in connection with one of its mutation carriers – the famous American actress Angelina Jolie – is in affected individuals mutated from their birth in one of its two copies, which substantially increases the risk that the other copy will also mutate and initiate a change from normal into tumourous cells.
In each of our cells, tens of thousands of DNA alterations occur every day, and these must be corrected. The task of the BRCA1 protein is to protect the genome against irreversible harmful changes and mutations by the activation of complex DNA damage repair pathways. If this protein is not available, or is not functional, cells are forced to repair the damage purely using a kind of backup (alternative) pathway in which an enzyme called PARP plays a key role. The system of maintaining genetic integrity is then generally compromised. This also implies that defects in genes, such as BRCA1, involved in the repair of damaged DNA increase the risk of genetic instability and tumorigenesis. In addition, due to the disabled BRCA1 gene, tumour cells in these patients actually have only one of the basic DNA repair pathways working. This weakness of a mutated tumour is targeted by one of the most promising research directions in modern anticancer therapy, known as "synthetic lethality". The phenomenon is based on the observation that killing cells requires the simultaneous occurrence of defects in both mutually substituting mechanisms – in this case the dysfunction of the BRCA1 and PARP as well.
Many years of research resulted in the introduction into clinical practice of a new drug, olaparib (Lynparza), which is an PARP protein inhibitor. So far, this completely new drug has been primarily designed for the treatment of ovarian cancer with mutations in the BRCA1 and BRCA2 genes. This drug blocks the function of the DNA repair pathway, dependent on the PARP enzyme in all cells of the body, i.e. it temporarily deprives them of that backup correction system. Healthy cells take virtually no notice, but the tumour cells have nothing other than the backup system available, so they therefore start to accumulate DNA damage with fatal consequences. The discovery of synthetic lethality, olaparib and similar compounds led to a completely new and revolutionary concept of specific cancer treatment. Clinical trials were therefore started very quickly with promising results, also for other types of cancer.
However, cancer is a sneaky enemy and it became clear relatively quickly that out of millions of differently mutated tumour cells, there are always some which are able to adapt and find an improvised pathway to the DNA damage repair. This means that they avoid excessive chromosomal instability which would otherwise inhibit their further growth. In the case of olaparib, a tumour adapts to treatment either by at least a partial correction of the mutated BRCA1 gene (the "reverse mutation") or its function is bypassed by disabling some of the other regulatory genes. As a result, after a temporary improvement, the disease returns, now however in an olaparib-resistant form. Using a cleverly designed experiment, professor Rottenberg's team from the Netherlands Cancer Institute discovered one of the ways in which a non-functional BRCA1 gene can be bypassed and the DNA repair mechanism restarted in genetically modified mice with a BRCA1 mutation. It turned out that one of the genes which can "switch off" these cells and therefore survive the treatment with olaparib, i.e. become resistant to this drug, is a regulatory protein known as REV7. However, what works in mice does not always work in humans. The team therefore asked professor Jiri Bartek and his Olomouc laboratory to validate the discovery on human cells and also to help reveal the molecular mechanism of how tumour cells actually bypass the absence of the functional BRCA1 protein by switching off REV7. A series of experiments involving various genetic manipulations associated with advanced microscopy performed at IMTM showed that REV7 has a completely unexpected new function of switching between the damaged DNA repair systems. It is the loss of the REV7 gene in tumours susceptible to treatment with olaparib, with defects in the BRCA1 gene, which allows the overall system adaptation and the development of unwanted resistance to this PARP inhibitor. Thanks to the joint work of the researchers, REV7 has recently ranked among proteins with more or less known functions which respond to DNA breaks and bind to damaged areas in a precisely described hierarchical order.
The mechanistic insight into the resistance to olaparib has numerous implications for patients treated with this new drug. We expect that REV7, as a biomarker, will enable the more accurate prediction of therapeutic response to the entire group of PARP inhibitors and support better a selection of the most appropriate patients. REV7 is also a promising molecular target, the therapeutic influence of which could increase the efficiency of BRCA1-deficient tumour treatment. Due to the promising results of clinical trials for other cancers, it can be expected that treatment with PARP inhibitors will be one of the widely used therapeutic strategies in the future. One indisputable advantage, in comparison with most of the existing cytostatics, is its minimum side effects on healthy tissue. Resistance to this group of drugs will therefore represent rather a serious problem in the treatment of patients with cancer, and the publication described is one of the first steps towards its resolution.
Tel.: + 420 585 63 2246
Ústav molekulární a translační medicíny (Institute of Molecular and Translational Medicine)
Lékařské fakulty Univerzity Palackého v Olomouci (at the Medical Faculty of Palacky University in Olomouc)
779 00 Olomouc