Phd. Ceremony Ms. Krajewska, M. Targeting homologous recombination repair in cancer cells

Conventional radiotherapy and chemotherapy target tumour cells by inducing DNA damage. Their combined application has contributed to increased survival and cure rates in numbers of patients. However, overall poor efficacy and systemic adverse effects of high doses of radio-/chemotherapy point to an urgent need for improvement. Limitations of these treatment modalities can be partially explained by the activity of DNA repair pathways that allow cancer cells to counteract the therapeutic effect of radio- and chemotherapy. One especially important DNA repair pathway in this respect is homologous recombination (HR) repair. HR repair is used to accurately resolve highly cytotoxic DNA double strand breaks (DSB). This repair pathway is found compromised in various cancers, including hereditary breast and ovarian cancer. Specifically, hereditary breast and ovarian cancers with germ line mutations in the BRCA1/2 genes show defects in HR repair. Intriguingly, tumour cells with defective HR repair show increased sensitivity to DNA damaging agents including ionizing radiation as well as specific chemotherapeutics. These observations suggest that therapeutic inactivation of HR repair may sensitize HR-proficient tumour cells to radio-/chemotherapy and thereby improve therapeutic options for various cancer types. In this thesis, we investigated pathways that regulate the efficiency of HR repair with the aim to uncover how HR repair can be therapeutically inactivated in cancer cells to enhance the cytotoxic effects of radio- and chemotherapy. Additionally, we identified vulnerabilities of HR-deficient tumour cells and tested whether these could be exploited for targeted cancer therapy.