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

Abstract

Key Points• Pevonedistat (MLN4924), a NEDD8-activating enzyme inhibitor, is active in MCL preclinical models and potentiates rituximab activity.• Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL.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 NEDD8-activating enzyme inhibitor in a panel of MCL cell lines, primary MCL tumor cells, and 2 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 the MCL cell lines with lower half-maximal inhibitory concentration (0.1-0.5 mM), pevonedistat induced G1-phase cell cycle arrest, downregulation of Bcl-xL levels, decreased nuclear factor (NF)-kB 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 2 MCL-bearing mouse models when compared with controls. Pevonedistat in combination with rituximab led to improved survival compared with rituximab or pevonedistat monotherapy. Our data suggest that pevonedistat has significant activity in MCL preclinical models, possibly related to effects on NF-kB activity, Bcl-xL downregulation, and G1 cell cycle arrest. Our findings support further investigation of pevonedistat with or without rituximab in the treatment of MCL. (Blood. 2016;127(9):1128-1137

Pevonedistat, a NEDD8‐activating enzyme inhibitor, induces apoptosis and augments efficacy of chemotherapy and small molecule inhibitors in pre‐clinical models of diffuse large B‐cell lymphoma

“…Significant survival benefit was noted in mouse models with pevonedistat alone or in combination with cytarabine or ibrutinib when compared with cytarabine or ibrutinib monotherapy. In contrast to what we observed in mantle cell lymphoma (MCL) pre‐clinical models [23], pevonedistat did not consistently improve anti‐tumor activity of rituximab in DLBCL.…”

Activity of TAS4464, a novel NEDD8 activating enzyme E1 inhibitor, against multiple myeloma via inactivation of nuclear factor κB pathways

“…Similarly, we found that NF‐κB inhibition occurred earlier than PI3K/mTOR signaling suppression upon NAE inhibition; that is, the transcription of NF‐κB‐targeted genes was downregulated after 4 hours of treatment with TAS4464 in cell lines KMS‐11, KMS‐12‐BM, KMS‐26 and MM.1S (Figure C). Further studies are needed to examine the extent to which the inhibition of each pathway is involved in the anti–MM activities of these compounds; however, MLN4924 rapidly increased the levels of p‐IκBα and p‐p100 in MM cells (Figure ) and is reported to inhibit the NF‐κB pathway in other hematological malignancies such as diffuse large B‐cell lymphoma and B‐cell chronic lymphocytic leukemia …”

NF-κB signaling pathway and its potential as a target for therapy in lymphoid neoplasms

“…MLN4924 can inhibit DLBCL cell line growth including ABC and GCB subtypes and can inhibit ABC-DLBCL tumors in xenograft mice models [157]. Another study found that MLN4924 is active in MCL and improves rituximab activity in vivo patient care [158]. In a phase I study, it was shown that 71% of 42 patients with relapsed and/or refractory lymphoma who had ≥1 post-baseline disease assessment achieved stable disease.…”