Abstract B92: Nedd8-activating enzyme inhibitor MLN4924 provides synergy in nonclinical models with mitomycin C through interactions with ATR, BRCA1/BRCA2 and chromatin dynamics pathways.

MLN4924 is an investigational small molecule inhibitor of the Nedd8-activating enzyme (NAE) currently in Phase 1 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 standards of care, including other DNA damaging agents. We studied the interaction of MLN4924 with other DNA damaging agents in a panel of 4 cell lines and found that mitomycin C, cisplatin, carboplatin, cytarabine, ultraviolet radiation, SN-38, and gemcitabine demonstrated synergy in combination with MLN4924 in at least 1 cell line. Further testing in xenograft-bearing mice demonstrated synergy of MLN4924 with mitomycin C and with carboplatin, and additivity with gemcitabine. Based in part on this data, MLN4924 is currently being evaluated in a Phase 1b trial ([NCT01862328][1]) with 3 combination arms: MLN4924 + carboplatin and paclitaxel, MLN4924 + gemcitabine, and MLN4924 + docetaxel. To evaluate the mechanism of synergy between MLN4924 and mitomycin C, in vitro experiments with RNAi were performed. Depletion of genes within the ATR and BRCA1/BRCA2 pathways, chromatin modification, and transcription-coupled repair reduced the synergy between mitomycin C and MLN4924. 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 be applied to additional combinations currently under clinical evaluation. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):B92. Citation Format: Eric S. Lightcap, Khristofer Garcia, Jonathan L. Blank, David C. Bouck, Xiaozhen J. Liu, Greg Hather, Allison Berger, Katherine Cosmopoulos, Michael P. Thomas, Mike Kuranda, Michael D. Pickard, Ray Liu, Syamala Bandi, Peter G. Smith. Nedd8-activating enzyme inhibitor MLN4924 provides synergy in nonclinical models with mitomycin C through interactions with ATR, BRCA1/BRCA2 and chromatin dynamics pathways. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr B92. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01862328&atom=%2Fmolcanther%2F12%2F11_Supplement%2FB92.atom