PARP1 Trapping by PARP Inhibitors Drives Cytotoxicity in Both Cancer Cells and Healthy Bone Marrow.

摘要: PARP inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA-associated breast cancer, ongoing studies are exploring additional indications combinations with other agents. trap onto damaged chromatin when combined temozolomide methyl methanesulfonate, but clinical relevance these findings remains unknown. trapping has thus far undetectable in cells treated alone. Here, we evaluate contribution to tolerability efficacy monotherapy setting. We developed a novel implementation proximity ligation assay detect chromatin-trapped PARP1 at single-cell resolution higher sensitivity throughput than previously reported methods. further demonstrate that inhibitor-induced appears drive single-agent cytotoxicity healthy human bone marrow, indicating toxicity trapped complexes is not restricted homologous recombination deficiency. Finally, show dramatically different potencies exhibit comparable tumor growth inhibition MTDs xenograft model BRCA1-mutant triple-negative cancer. These results consistent emerging data suggest inverse relationship between potency may limit potential therapeutic advantage potent activity. IMPLICATIONS: contributes both activity be limited.