Abstract IA08: Synthetic viability due to BRCA2 and PARP1 loss

It is very well established that BRCA1 and BRCA2 deficient cells are hypersensitive to PARP inhibitors (PARPi) due to synthetic lethality. Because Parp1 parylates proteins involved in a wide range of biological processes, we hypothesized that inhibiting PARP activity may have detrimental effect on cells that are HR proficient and do not undergo synthetic lethality. We have demonstrated that although Brca2 null ES cells are not viable, they can survive after ES cells expressing a conditional allele of Brca2 are treated with olaparib prior to Cre-mediated deletion of the conditional allele. We also found that while Parp1 loss does not rescue the HR defect, surprisingly, it rescues the MRE11-mediated degradation of stalled replication forks associated with BRCA2 loss. Interestingly, we found that reducing MRE11 activity/levels also rescues the lethality of Brca2ko/ko ES cells. Similar to the ES cells, we observe fork protection in mouse B-cells deficient in Parp1 and Brca2 as well as in human MCF10A cells.This unexpected functional interaction between BRCA2 and PARP1 that results in synthetic viability can have profound clinical implications: use of PARP inhibitors for cancer prevention in BRCA-mutation carriers is being explored based on the assumption that PARPi would be innocuous in normal cells. Our findings raise concerns that when patients are treated with PARPi, not only are the tumor cells killed, but normal cells can also be affected. In BRCA-mutation carriers, the majo...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Synthetic Lethality and Viability: Oral Presentations - Invited Abstracts Source Type: research