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Pevonedistat, a NEDD8 activating enzyme inhibitor, is active in mantle cell lymphoma and enhances rituximab activity in vivo

Natalie M. Czuczman, Matthew J. Barth, Juan Gu, Vishala Neppalli, Cory Mavis, Sarah E. Frys, Qiang Hu, Song Liu, Pavel Klener, Petra Vockova, Myron S. Czuczman and Francisco J. Hernandez-Ilizaliturri

Key points

  • Pevonedistat (MLN4924), a NEDD8 Activating Enzyme (NAE) inhibitor is active in MCL preclinical models and potentiates rituximab activity.

  • Our findings support further investigation of pevonedistat +/- rituximab in the treatment of MCL.

Abstract

Mantle cell lymphoma (MCL) is characterized by an aggressive clinical course and inevitable development of refractory disease stressing the need to develop alternative therapeutic strategies. To this end, we evaluated pevonedistat (MLN4924), a novel, potent and selective NAE inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and two distinct murine models of human MCL. Pevonedistat exposure resulted in a dose-, time-, and caspase-dependent cell death in the majority of the MCL cell lines and primary tumor cells tested. Of interest, in MCL cell lines with lower IC50 (0.1-0.5µM), pevonedistat induced G1 phase cell cycle arrest, down-regulation of Bcl-XL levels, decreased NFκB activity, and apoptosis. In addition, pevonedistat exhibited additive/synergistic effects when combined with cytarabine, bendamustine or rituximab. In vivo, as a single agent, pevonedistat prolonged the survival of two MCL-bearing mouse models when compared to controls. Pevonedistat in combination with rituximab led to improved survival compared to rituximab or pevonedistat monotherapy. Our data suggest that, pevonedistat has significant activity in MCL pre-clinical models; possibly related to effects on NF-κB activity, Bcl-XL down-regulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat +/- rituximab in the treatment of MCL.

  • Submitted April 15, 2015.
  • Accepted November 30, 2015.