CANCER cell resistance to PARP inhibitor therapy could be overcome following the discovery of various mechanisms that lay behind this resistance. The study, conducted by an international research team under the co-direction of the University of Bern, Bern, Switzerland and the Netherlands Cancer Institute (NKI), has identified additional therapeutic options for patients whose cancer has reappeared after initially being treated successfully with PARP inhibitors.
Resistance to PARP Inhibitors
Certain cancers, particularly ovarian and breast, are associated with defects in the DNA repair proteins BRCA1 and BRCA2. In these cases, treatment with PARP inhibitors causes the cancer cells to die off while the healthy body cells survive. In many cases, however, the cancer develops resistance to this therapy. A study was therefore undertaken to try and understand the mechanisms that underpin this resistance.
Mechanisms of Resistance
Using CRISPR/Cas9 gene scissors and targeted silencing of genes, the team genetically modified millions of BRCA-mutated cancer cells before treating them with PARP inhibitors. The cells that had survived the treatment were found to have developed resistance due to certain genetic changes. “The changes in these cells then indicated to us which genes are involved in the development of a resistance,” explained Prof Sven Rottenberg, University of Bern.
After cultivating the tumour cells in a three-dimensional matrix to observe this taking place, they discovered that other proteins also involved in the repair of DNA breaks need to be functioning properly for PARP inhibitor treatment to be successful; if they are not, then resistance develops.
These findings have revealed additional treatment opportunities for those patients in whom resistance has developed. “In our models, we have seen that the tumours that are resistant the treatment by PARP inhibitors, due to the deficiency of other repair proteins, can be fought with radiotherapy or already established anti-cancer drugs such as temozolamide. This opens up therapeutic options for patients in which the cancer has reappeared after an initially successful treatment with PARP inhibitors,” added Prof Rottenberg.
The study has also provided a greater understanding of the fundamental mechanisms of DNA repair, which could have major implications for future research in this field.
The group are now continuing to study resistance in cancer caused by defective repair proteins, with the hope of finding new ways to overcome the problem.
James Coker, Reporter
For the source and further information about the study, click here.