Mariana Dias - ESR 12

Name:  Mariana Dias

Nationality:  Portuguese

Main Host Institution:  Netherlands Cancer Institute (NKI)

Academic Background:  I graduated  in Cell and Molecular Biology (NOVA University of Lisbon, Portugal). Next, I obtained my Master's degree in Molecular Medicine and Oncology (University of  Porto, Portugal). During my master studies, I came to NKI and joined the ‘ Telomere Damage and Cancer’ group  to do an internship, where I studied the role of BRCA1 complexes in DNA repair pathway choice and replication stress.

Project title:  Identification of genes that confer resistance to synthetic lethality drugs in BRCA1/2-deficient tumor cells

Project background:  Error-free repair of DNA double-strand breaks (DSBs) is achieved by homology directed repair (HDR), and both BRCA1 and BRCA2 are crucial for this process. Indeed, germline mutations in BRCA1/2 are responsible for a large proportion of hereditary breast and ovarian cancers. Poly-(ADP-ribose) polymerase (PARP) inhibitors (PARPis) selectively kill BRCA-deficient cells. This observation provided the impetus for PARPis to be tested clinically, which has recently resulted in the approval of the first PARPis for the treatment of patients with BRCA-deficient tumors. Although this approach has shown promise, efficacy is limited by drug resistance.

Project Aim:  We aim to conduct in vitro functional genetic screens to uncover new mechanisms of resistance to PARPis and to find promising strategies to overcome resistance. Using this approach, we have already shown that loss of 53BP1 or REV7 confers resistance to PARPis. We will use the same approach to identify genes that confer resistance to PARPis and drugs developed by SYNTRAIN beneficiaries. After identifying the top hits from the above screens, we will validate them and explore the molecular function of selected validated hits.

Expected outcome:  We expect to unveil new genes that are causal to the resistance phenotype in order to get  insights into the molecular mechanisms leading to drug resistance and to and to uncover new strategies to reverse resistance.

Contact:  Jos Jonkers group, NKI