Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis
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Cody Paiva1,*, J. Claire Godbersen2,*, Taylor Rowland1, Olga V. Danilova3, Christopher Danes4, Allison Berger4, Alexey V. Danilov1
1Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA
2Geisel School of Medicine at Dartmouth, Department of Medicine, Hanover, NH, USA
3VA Portland Healthcare System, Department of Pathology and Laboratory Medicine, Portland, OR, USA
4Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, MA, USA
*These authors have contributed equally to this work
Alexey V. Danilov, email: [email protected]
Keywords: lymphoma, neddylation, CLL, TRAIL
Received: September 13, 2016 Accepted: January 07, 2017 Published: February 03, 2017
While death receptor ligands (Fas and TRAIL) kill chemoresistant tumor cell lines, related therapies have limited clinical efficacy as single agents. Death receptor signaling is modulated by nuclear factor-κB (NFκB), a family of transcription factors which are constitutively active in B-cell malignancies. We and others have shown that pevonedistat, an investigational inhibitor of the NEDD8-activating enzyme, abrogates NFκB activity in B-cell neoplasia. Here we demonstrate that diffuse large B-cell lymphoma, particularly activated B-cell type, and primary chronic lymphocytic leukemia cells are re-sensitized to extrinsic apoptosis by pevonedistat. Pevonedistat enhanced caspase-8 processing following death receptor ligation, and downmodulated cFLIP, a NFκB-regulated protease-deficient caspase homolog. However, treatment with pevonedistat did not modulate death-inducing signaling complex in neoplastic B-cells, suggesting that they were sensitized to death ligands through the mitochondrial pathway. Our data provide rationale for further development of pharmacologic agents including pevonedistat in strategies which enhance death receptor signaling in lymphoid malignancies.
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