title: Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor.
abstract: Radiotherapy is used in locally advanced pancreatic cancers in which it can improve survival in combination with gemcitabine. However, prognosis is still poor in this setting in which more effective therapies remain needed. MLN4924 is an investigational small molecule currently in phase I clinical trials. MLN4924 inhibits NAE (NEDD8 Activating Enzyme), a pivotal regulator of the E3 ubiquitin ligase SCF (SKP1, Cullins, and F-box protein), that has been implicated recently in DNA damage and repair. In this study, we provide evidence that MLN4924 can be used as an effective radiosensitizer in pancreatic cancer. Specifically, MLN4924 (20-100 nmol/L) effectively inhibited cullin neddylation and sensitized pancreatic cancer cells to ionizing radiation in vitro with a sensitivity enhancement ratio of approximately 1.5. Mechanistically, MLN4924 treatment stimulated an accumulation of several SCF substrates, including CDT1, WEE1, and NOXA, in parallel with an enhancement of radiation-induced DNA damage, aneuploidy, G(2)/M phase cell-cycle arrest, and apoptosis. RNAi-mediated knockdown of CDT1 and WEE1 partially abrogated MLN4924-induced aneuploidy, G(2)/M arrest, and radiosensitization, indicating a causal effect. Furthermore, MLN4924 was an effective radiosensitizer in a mouse xenograft model of human pancreatic cancer. Our findings offer proof-of-concept for use of MLN4924 as a novel class of radiosensitizer for the treatment of pancreatic cancer.
authors.affiliation: Division of Radiation and Cancer Biology, Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Dongping
authors.initials: D
authors.lastname: Wei
authors.forename: Hua
authors.initials: H
authors.lastname: Li
authors.forename: Jie
authors.initials: J
authors.lastname: Yu
authors.forename: Jonathan T
authors.initials: JT
authors.lastname: Sebolt
authors.forename: Lili
authors.initials: L
authors.lastname: Zhao
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Lawrence
authors.forename: Peter G
authors.initials: PG
authors.lastname: Smith
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Morgan
authors.forename: Yi
authors.initials: Y
authors.lastname: Sun
mesh_terms: D000782:Aneuploidy; D000818:Animals; D001483:Base Sequence; D002455:Cell Division; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology / Q000627:therapeutic use*; D004249:DNA Damage; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D005455:Fluorescent Antibody Technique; D016195:G2 Phase; D006801:Humans; D000075687:NEDD8 Protein; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000532:radiotherapy; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D034741:RNA, Small Interfering; D011836:Radiation Tolerance / Q000187:drug effects*; D014452:Ubiquitins / Q000037:antagonists & inhibitors*; D023041:Xenograft Model Antitumor Assays
chemical_list: D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D034741:RNA, Small Interfering; D014452:Ubiquitins; C539933:pevonedistat
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