Abstract B64: Schlafen 11 (SLFN11) irreversibly blocks cell cycle recovery independently of ATR following replicative damage by poly(ADPribose) polymerase inhibitors

Abstract

Abstract PARP inhibitors kill cancer cells by trapping PARP-DNA complexes, with talazoparib the inhibitor with the highest PARP trapping activity. Genomic analyses across the 60 cancer cell lines of the National Cancer Institute (NCI-60) revealed a highly significant correlation between SLFN11 expression and sensitivity to talazoparib. The causal role of SLFN11 was established after generating four SLFN11-knockout cell lines (prostate DU145, Ewing EW8, leukemia CCRF-CEM and MOLT4) by CRISPR/Cas9 system, and finding that SLFN11 inactivation conferred high resistance to both talazoparib and olaparib. Resistance was caused neither by impaired drug penetration nor by hyperactivation of homologous recombination, as demonstrated in BRCA2-inactivated cells. SLFN11-proficient cells were irreversibly arrested in S phase by talazoparib treatment. Although ATR is the key regulator of the intra-S phase checkpoint, the addition of the ATR inhibitor (VE-821) did not release the replication arrest in SLFN11-proficient cells. By contrast, SLFN11-deficient cells treated with talazoparib reached G2, and their cell cycle and replication arrest was reversed by ATR inhibition. The combination of VE-821 with talazoparib or olaparib was highly synergistic with the greater synergy in the SLFN11-deficient cells. Our study reveals that SLFN11 acts as a novel DNA damage response gene for replicative DNA damage, and that SLFN11 inactivation, which is common in cancer cells, is a novel mechanism of resistance for PARP inhibitors, which can be mitigated by combining PARP and ATR inhibitors. Citation Format: Junko Murai, Yves Pommier. Schlafen 11 (SLFN11) irreversibly blocks cell cycle recovery independently of ATR following replicative damage by poly(ADPribose) polymerase inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B64.