title: Disrupting protein NEDDylation with MLN4924 is a novel strategy to target cisplatin resistance in ovarian cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors: Institute for Drug Development, Cancer Therapy and Research Center at The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
authors: Steffan T
authors: ST
authors: Nawrocki
authors: Kevin R
authors: KR
authors: Kelly
authors: Peter G
authors: PG
authors: Smith
authors: Claudia M
authors: CM
authors: Espitia
authors: Anthony
authors: A
authors: Possemato
authors: Sean A
authors: SA
authors: Beausoleil
authors: Michael
authors: M
authors: Milhollen
authors: Stephen
authors: S
authors: Blakemore
authors: Michael
authors: M
authors: Thomas
authors: Allison
authors: A
authors: Berger
authors: Jennifer S
authors: JS
authors: Carew
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000494:pharmacology*; D003517:Cyclopentanes / Q000494:pharmacology*; D004249:DNA Damage / Q000235:genetics; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D024101:Mitochondrial Proteins; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D020543:Proteome; D011743:Pyrimidines / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D014410:Tumor Stem Cell Assay; D023041:Xenograft Model Antitumor Assays
chemical_list: D051017:Apoptosis Regulatory Proteins; C096820:BIK protein, human; D003517:Cyclopentanes; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D016328:NF-kappa B; D020543:Proteome; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D002945:Cisplatin; C539933:pevonedistat