Olomouc Discovery Explains Tumour Resistance to New Generation of Drugs
Photos: BRCA1 protein: The accumulation of the BRCA1 protein (green) where DNA was damaged by UV laser (horizontal lines) in tumour cell nuclei (blue). The control signal of the g-H2AX protein, as a general marker of double-strand DNA breaks, is marked in red.
A member of the international team and co-author of the study, Martin Mistrík
A new mechanism by which cancer cells acquire resistance to antitumour treatment has been identified by scientists from the Institute of Molecular and Translational Medicine (IMTM) at the Palacký University Faculty of Medicine in collaboration with their colleagues from the Netherlands. The promising findings of their research that may contribute to more targeted therapy of ovarian and breast cancers have been confirmed by the team under the most cited Czech scientist, Jiří Bártek, in their Olomouc laboratories. Their findings were published in the prestigious journal Nature.
Their work focussed on tumours caused by a genetic disposition to a hereditary form of ovarian and breast cancer. The BRCA1 gene is responsible, mutated in affected individuals from their birth in one of its two copies. “The risk that the other copy will also mutate is thus considerably increased. A healthy cell loses its ability of error-free repair of the DNA damage and starts using a kind of a back-up correction system, an alternative repair pathway, which accumulates mutations to a large extent. The normal cell then changes into a tumourous one,” explained a member of the international team and a co-author of the study, Martin Mistrík, from Palacký University.
A new drug, olaparib (Lynparza), has been recently introduced into clinical practice for the treatment of ovarian cancer with hereditary BRCA1 genetic mutations, designed to block the function of the DNA back-up repair pathways. “Healthy cells take virtually no notice, whereas the tumorous cells begin accumulating DNA damage with fatal consequences,” said Mistrík. However, the promising direction of this antitumour therapy has been complicated by a recent finding that among the millions of variously mutated tumour cells, there are always some that resist the treatment, adapt, and subsequently cause a relapse. As a result, after a temporary improvement, the disease returns, now however in a form resistant to the drug.
One of the ways how the cells can “switch off” and survive the olaparib treatment has been discovered by the team of Prof Rottenberg from the Netherlands Cancer Institute. Their experiment on genetically modified mice with BRCA1 mutation proved that one of the factors why the cells become resistant to the drug is the loss of a regulatory protein REV7, also known as MAD2L2.
The validation on human cells was conducted by Prof Jiří Bártek and his Olomouc laboratory team. Their experimental work helped 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,” said Mistrík.
Scientists assume that this Olomouc discovery has numerous implications for patients treated with this new drug and for the solution of the serious problem of resistance to antitumour treatment. “We expect that REV7, as a biomarker, will enable the more accurate prediction of therapeutic response to the entire group of PARP inhibitors and better support a selection of the most appropriate patients,” emphasised Mistrík. The results of the research are also promising in terms of further development of substances for more targeted antitumour treatment with minimum side effects on healthy tissues.
“The study of the mechanisms of tumour resistance is essential in finding alternative ways of treatment. The IMTM has been dealing with this issue on a long-term basis, and the publication of our findings in such a prestigious journal is the best proof of their significance and quality,” concluded the IMTM Director, Marián Hajdúch.
