RT Journal Article
SR Electronic
T1 PARP1 trapping by PARP inhibitors drives cytotoxicity both in cancer cells and healthy bone marrow
JF Molecular Cancer Research
JO Mol Cancer Res
FD American Association for Cancer Research
SP molcanres.0138.2018
DO 10.1158/1541-7786.MCR-18-0138
A1 Hopkins, Todd A
A1 Ainsworth, William B
A1 Ellis, Paul A
A1 Donawho, Cherrie K
A1 DiGiammarino, Enrico L.
A1 Panchal, Sanjay C.
A1 Abraham, Vivek C.
A1 Algire, Mikkel A
A1 Shi, Yan
A1 Olson, Amanda M.
A1 Johnson, Eric F.
A1 Wilsbacher, Julie L.
A1 Maag, David
YR 2018
UL http://mcr.aacrjournals.org/content/early/2018/11/14/1541-7786.MCR-18-0138.abstract
AB Abstract: Poly (ADP-ribose) polymerase (PARP) inhibitors have recently been approved as monotherapies for the treatment of recurrent ovarian cancer and metastatic BRCA-associated breast cancer, and ongoing studies are exploring additional indications and combinations with other agents. PARP inhibitors trap PARP onto damaged chromatin when combined with temozolomide and methyl methanesulfonate, but the clinical relevance of these findings remains unknown. PARP trapping has thus far been undetectable in cancer cells treated with PARP inhibitors alone. Here we evaluate the contribution of PARP trapping to the tolerability and efficacy of PARP inhibitors in the monotherapy setting. We developed a novel implementation of the proximity ligation assay to detect chromatin-trapped PARP1 at single-cell resolution with higher sensitivity and throughput than previously reported methods. We further demonstrate that the PARP inhibitor-induced trapping appears to drive single-agent cytotoxicity in healthy human bone marrow, indicating that the toxicity of trapped PARP complexes is not restricted to cancer cells with homologous recombination deficiency (HRD). Finally, we show that PARP inhibitors with dramatically different trapping potencies exhibit comparable tumor growth inhibition at maximum tolerated doses in a xenograft model of BRCA1-mutant triple negative breast cancer. These results are consistent with emerging clinical data and suggest that the inverse relationship between trapping potency and tolerability may limit the potential therapeutic advantage of potent trapping activity. Implications: PARP trapping contributes to single-agent cytotoxicity of PARP inhibitors in both cancer cells and healthy bone marrow, and the therapeutic advantage of potent trapping activity appears to be limited.