Abstract
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. Finally, we show that PARP inhibitors with dramatically different trapping potencies exhibit comparable tumor growth inhibition at MTDs 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.
Highlights
The recent approvals of the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) for the treatment of BRCA-mutated ovarian cancer [1] and niraparib (Zejula) for the treatment of recurrent ovarian cancer with or without BRCA mutation [2] are important benchmarks in over 50 years of research since the initial discovery of this important class of enzymes
Studies have shown that PARP inhibitors with similar catalytic potency can differ in their ability to induce PARP1 trapping [6, 8]; the unique potency and binding residence time exhibited by the PARP inhibitor talazoparib confound interpretation of the relationship between trapping and cytotoxic potency
Talazoparib produces substantially more PARP1 trapping and DNA damage potentiation activities in cells treated with methyl methanesulfonate (MMS; Fig. 1D and E)
Summary
The recent approvals of the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) for the treatment of BRCA-mutated ovarian cancer [1] and niraparib (Zejula) for the treatment of recurrent ovarian cancer with or without BRCA mutation [2] are important benchmarks in over 50 years of research since the initial discovery of this important class of enzymes. The enzymatic function of PARP1, known as PARylation, is the synthesis of ADP-ribose polymers (PAR) that covalently modify host proteins or its own automodification domain [3]. When DNA is damaged, PARP1 binds the damage site and catalyzes synthesis of PAR that recruits host DNA repair proteins. AutoPARylation of PARP1 induces an electrostatic destabilization and dissociation from the DNA damage site which enables repair proteins to localize to the lesion [4, 5]. When DNA damage occurs in the presence of a AbbVie, Inc., North Chicago, Illinois
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