Abstract
MLN4924 is an investigational small-molecule inhibitor of the Nedd8-activating enzyme currently in phase I clinical trials. MLN4924 induces DNA damage via rereplication in most cell lines. This distinct mechanism of DNA damage may affect its ability to combine with standard-of-care agents and may affect the clinical development of MLN4924. As such, we studied its interaction with other DNA-damaging agents. Mitomycin C, cisplatin, cytarabine, UV radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in vitro. The combination of mitomycin C and MLN4924 was shown to be synergistic in a mouse xenograft model. Importantly, depletion of genes within the ataxia telangiectasia and Rad3 related (ATR) and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. In addition, comet assay demonstrated increased DNA strand breaks with the combination of MLN4924 and mitomycin C. Our data suggest that mitomycin C causes stalled replication forks, which when combined with rereplication induced by MLN4924 results in frequent replication fork collisions, leading to cell death. This study provides a straightforward approach to understand the mechanism of synergy, which may provide useful information for the clinical development of these combinations.
Highlights
MLN4924 is being developed as an inhibitor of the Nedd8-activating enzyme [1] and is currently in phase I clinical trials
Nedd8 is a small ubiquitin-like protein in which the best characterized role is the activation of a class of E3 ubiquitin ligases known as cullin RING ligases
Our results suggest that mitomycin C increases the frequency of replication fork collision induced by MLN4924 and that the BRCA1–claspin–ATR–Chk1 pathway plays an important role in the response to these collisions
Summary
MLN4924 is being developed as an inhibitor of the Nedd8-activating enzyme [1] and is currently in phase I clinical trials. Nedd is a small ubiquitin-like protein in which the best characterized role is the activation of a class of E3 ubiquitin ligases known as cullin RING ligases Multiple studies have demonstrated the importance of the induction of rereplication, resulting in DNA damage, to the mechanism of cell death by MLN4924 [3,4,5]. CRLs are known to be involved in the regulation of multiple DNA replication and repair pathways, including nucleotide excision repair, histone modification, Authors' Affiliations: Departments of 1Discovery, 2Clinical Biostatistics, and 3Information Technology, Takeda Pharmaceuticals International Co., Cambridge, Massachusetts. Cosmopoulos: Agios Pharmaceuticals, Cambridge, Massachusetts; and current address for M.P. Thomas and P.G. Smith, H3 Biomedicine, Inc., Cambridge, Massachusetts
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