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Purpose: Ovarian cancer has the highest mortality rate of all female reproductive malignancies. Drug resistance is a major cause of treatment failure and novel therapeutic strategies are urgently needed. MLN4924 is a NEDDylation inhibitor currently under investigation in multiple phase I studies. We investigated its anticancer activity in cisplatin-sensitive and -resistant ovarian cancer models. Experimental Design: Cellular sensitivity to MLN4924/cisplatin was determined by measuring viability, clonogenic survival, and apoptosis. The effects of drug treatment on global protein expression, DNA damage, and reactive oxygen species generation were determined. RNA interference established natural born killer/bcl-2–interacting killer (NBK/BIK) as a regulator of therapeutic sensitivity. The in vivo effects of MLN4924/cisplatin on tumor burden and key pharmacodynamics were assessed in cisplatin-sensitive and -resistant xenograft models. Results: MLN4924 possessed significant activity against both cisplatin-sensitive and -resistant ovarian cancer cells and provoked the stabilization of key NEDD8 substrates and regulators of cellular redox status. Notably, MLN4924 significantly augmented the activity of cisplatin against cisplatin-resistant cells, suggesting that aberrant NEDDylation may contribute to drug resistance. MLN4924 and cisplatin cooperated to induce DNA damage, oxidative stress, and increased expression of the BH3-only protein NBK/BIK. Targeted NBK/BIK knockdown diminished the proapoptotic effects of the MLN4924/cisplatin combination. Administration of MLN4924 to mice bearing ovarian tumor xenografts significantly increased the efficacy of cisplatin against both cisplatin-sensitive and -resistant tumors. Conclusions: Our collective data provide a rationale for the clinical investigation of NEDD8-activating enzyme (NAE) inhibition as a novel strategy to augment cisplatin efficacy in patients with ovarian cancer and other malignancies. Clin Cancer Res; 19(13); 3577–90. ©2013 AACR.

PURPOSE: Ovarian cancer has the highest mortality rate of all female reproductive malignancies. Drug resistance is a major problem that limits overall survival and novel therapeutic strategies are urgently needed. The inappropriate loss of several NEDD8-cullin-RING ubiquitin ligase (CRL) targets has been linked to cancer progression and drug resistance, suggesting that this pathway may be a promising new therapeutic target. MLN4924 is a first-in-class NEDD8 activating enzyme (NAE) inhibitor currently under investigation in multiple clinical studies. We investigated its anticancer activity and pharmacodynamic effects in cisplatin-sensitive and cisplatin-resistant ovarian cancer models. EXPERIMENTAL PROCEDURES: Cellular sensitivity to MLN4924/cisplatin was determined by measuring viability, senescence, and apoptosis. The effects of drug treatment on global protein expression, DNA damage, and reactive oxygen species generation were determined. RNA interference approaches were used to identify and validate regulators of therapeutic sensitivity. The in vivo effects of MLN4924/cisplatin on tumor burden and key pharmacodynamic endpoints were assessed in cisplatin-sensitive and -resistant xenograft models. RESULTS: Intrinsic resistance to cisplatin did not significantly impact the efficacy of MLN4924 against ovarian cancer cells, indicating that this agent may be useful for patients with platinum-resistant disease. Detailed pharmacodynamic analyses showed that treatment with MLN4924 induced the stabilization of key NEDD8 substrates and regulators of cellular redox status. Notably, cisplatin-resistant cells displayed significantly higher basal levels of NEDDylated cullins and NEDDylation activity than cisplatin-sensitive cells. Further investigation demonstrated that MLN4924 significantly augmented the activity of cisplatin against cisplatin-resistant cells. This suggests that aberrant NEDDylation may contribute to drug resistance and that targeting this pathway may be a promising strategy to restore chemosensitivity. MLN4924 and cisplatin cooperated to induce DNA damage, oxidative stress, and increased expression of the BH3-only protein NBK/BIK. Targeted NBK/BIK knockdown diminished the pro-apoptotic effects of the MLN4924/cisplatin combination. In addition, administration of MLN4924 to mice bearing ovarian tumor xenografts significantly increased the efficacy of cisplatin against both cisplatin-sensitive and cisplatin-resistant tumors. CONCLUSIONS: Our collective data provide a rationale for the clinical investigation of NAE inhibition as a novel strategy to augment cisplatin efficacy in patients with ovarian cancer and other malignancies where platinum-based chemotherapy is utilized. Citation Format: Steffan T. Nawrocki, Kevin R. Kelly, Claudia M. Espitia, and Jennifer S. Carew. TARGETING NEDDYLATION TO OVERCOME CISPLATIN RESISTANCE IN OVARIAN CANCER [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-102.