Due to the presence of mutations and copy number alterations in tumor suppressor genes (TSGs) that function in DNA repair in many cancers, these cells tend to rely on backup or alternative pathways to a higher degree than normal cells. Synthetic lethality typically ensues when these backup pathways are lost, and these synthetic lethal interactions between DNA repair genes can be exploited as an Achilles heel in the treatment of certain cancers. We are employing high throughput approaches to identify these synthetic vulnerabilities that can then be targeted for improved cancer care.
PARP inhibitors are widely used in treating homologous recombination (HR)-deficient (such as BRCA mutant) cancers; however, these treatments can often lead to resistance. We have performed several synthetic lethal screens to identify novel vulnerabilities of BRCA mutant cancer cell lines, especially following treatment with replication stress agents. In addition, we are performing ORFeome overexpression screens to identify potential resistance mechanisms to PARP inhibition in BRCA mutant cell lines. We intend to perform additional screens in more contexts and follow up on these studies to characterize some novel mechanisms of viability and/or resistance in BRCA mutant and other HR-deficient contexts.