Pevonedistat, a Nedd8-activating enzyme inhibitor, sensitizes neoplastic B-cells to death receptor-mediated apoptosis.
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.
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Cody
C
Paiva
Geisel School of Medicine at Dartmouth, Department of Medicine, Hanover, NH, USA.
J Claire
JC
Godbersen
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Taylor
T
Rowland
VA Portland Healthcare System, Department of Pathology and Laboratory Medicine, Portland, OR, USA.
Olga V
OV
Danilova
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, MA, USA.
Christopher
C
Danes
Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd., Cambridge, MA, USA.
Allison
A
Berger
Knight Cancer Institute, Oregon Health and Science University, Portland, OR, USA.
Alexey V
AV
Danilov
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D003517:Cyclopentanes / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016403:Lymphoma, Large B-Cell, Diffuse / Q000473:pathology*; D000075687:NEDD8 Protein; D011743:Pyrimidines / Q000494:pharmacology*; D053218:Receptors, Death Domain / Q000378:metabolism; D014452:Ubiquitins / Q000378:metabolism
D000970:Antineoplastic Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D053218:Receptors, Death Domain; D014452:Ubiquitins; C539933:pevonedistat
CLL; TRAIL; lymphoma; neddylation