• Traitements

  • Combinaison de traitements localisés et systémiques

  • Pancréas

Radiosensitization of human pancreatic cancer cells by MLN4924, an investigational NEDD8-activating enzyme inhibitor

Menée in vitro et à l'aide d'une xénogreffe, cette étude montre que la molécule MLN4924 peut augmenter la sensibilité des cellules cancéreuses du pancréas à la radiothérapie

Radiotherapy is used in locally advanced pancreatic cancers where it can improve survival in combination with gemcitabine. However, prognosis is still poor in this setting where 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 repair. In this study, we provide evidence that MLN4924 can be used as an effective radiosensitizer in pancreatic cancer. Specifically, MLN4924 (20-100 nM) effectively inhibited cullin neddylation and sensitized pancreatic cancer cells to ionizing radiation in vitro with a sensitivity enhancement ratio (SER) of ~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, G2/M phase cell cycle arrest and apoptosis. RNAi-mediated knockdown of CDT1 and WEE1 partially abrogated MLN4924-induced aneuploidy, G2/M arrest, and radiosensization, indicating a causal effect. Further, MLN4924 was an effective radiosensitizer in mouse xenograft models 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.

Cancer Research

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