Drug Target Discovery by Mapping Genome Maintenance with Genetic Interaction Screens

The breast cancer susceptibility genes BRCA1 and BRCA2, are potent tumor suppressors. The loss of these genes causes profound genomic instability due to their role in homologous recombination and replication fork management. While BRCA-deficient tumors initially respond well to standard-of-care therapies, such as cisplatin and PARP inhibitors (PARPi), tumors invariably acquire resistance to these agents and do recur, leaving patients with very few therapeutic options. It is therefore imperative that we identify new genetic vulnerabilities caused by BRCA1/2 mutations, as a means to identify new therapeutic targets for BRCA-deficient tumors. In my presentation, I will discuss our recent efforts in mapping genome maintenance pathways using genome-scale CRISPR/Cas9 screens in human cells, including BRCA synthetic lethality screens. I will highlight how our development of a genome stability network has identified potentially actionable synthetic lethal genetic interactions in BRCA-deficient cells. If I have time, I will also discuss our efforts to identify vulnerabilities to the DNA replication stress caused by cyclin E gene amplification, a potent oncogenic event. I will argue that somatic genetic screens in human cells are powerful tools to identify new therapeutic targets and uncover new aspects of the response to DNA damage in human cells