Ovarian cancer is the most deadly disease of the female reproductive tract and has historically been called the “silent killer.” Chemotherapy resistance and toxicity is one of the major barriers to cure ovarian cancer. Our study will test a novel strategy to sensitize ovarian cancer cells to a conventional chemotherapeutic drug. We found that ubiquitin-like protein Nedd8 plays an important role in DNA damage repair of ovarian cancer cells and the small molecule inhibitor of Nedd8 pathway, MLN4924 can suppress DNA damage repair. Therefore, MLN4924 can be used as the sensitizer for ovarian cancer chemotherapeutic drugs like cisplatin, which generates massive DNA damage to kill ovarian cancer cells. This study is of highly translational value by validating neddylation and its inhibitor MLN4924 as an attractive anti-cancer target and drug, respectively. If successful, translation of this novel finding to clinical trials is highly feasible. The completion of the pre-clinical studies described in this proposal will lead to the rational design of clinical trials including MLN4924 for the treatment of ovarian cancer with the final purpose of improving the quality and quantity of life of ovarian cancer patients, and converting this lethal cancer into a manageable disease.