Homologous recombination-deficient cancers: approaches to improve treatment and patient selection

In order for cells to divide, all the DNA in a cell must be copied and divided into two new cells. However, DNA in our cells is constantly dealing with different types of damage, either from factors outside (eg UV rays in sunlight) or inside the body (eg due to errors that occur during the copying of the DNA). To ensure that this damage does not lead to permanent changes, cells have DNA damage repair mechanisms. An important mechanism is homologous recombination (HR) that repairs double-stranded DNA breaks. Without this mechanism, cells cannot survive. However, some cancers have a defect in HR. This is a paradox, because healthy cells do not survive without HR, while these cancer cells apparently survive without HR. BRCA1 and BRCA2 are two important genes in HR and a BRCA1/2 mutation is associated with an increased risk to develop breast and ovarian cancer. In this thesis, models are used in which a BRCA1/2 defect is induced to study an HR defect in cancer. Since 2013, PARP inhibitors have been approved for the treatment of patients with BRCA1/2-mutated breast and ovarian cancer. However, a defect in HR can also be caused by other gene mutations and these patients could also benefit from PARP inhibitors. In this thesis, a test is validated to select the right patients for PARP inhibitor treatment. The working mechanisms of PARP inhibitors are also being investigated to make treatment even more effective. In addition, the immune system plays an important role in cancers with an HR defect. Some of these mechanisms are described and investigated.