Abstract IA08: Synthetic viability due to BRCA2 and PARP1 loss

Abstract

Abstract 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 majority of the cells that lose the wild-type allele undergo cell cycle arrest or apoptosis unless they acquire additional mutations in genes (the identity of which are unknown) that bypass such a response. Our work provides strong evidence that Parp1 inhibition contributes to the viability of BRCA2 deficient cells, a key step in the transformation of a normal cell to pre-neoplastic state. We have genetic evidence to show that Parp1 deficiency can contribute to tumorigenesis in mice. We found a significant increase in tumorigenesis in Brca2 conditional knockout mice (cko/cko) with K14Cre on a Parp1 heterozygous background compared to those on a Parp1 wild-type background. Citation Format: Shyam K. Sharan. Synthetic viability due to BRCA2 and PARP1 loss [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr IA08.