The NEDD8-activating enzyme inhibitor pevonedistat activates the eIF2α and mTOR pathways inducing UPR-mediated cell death in acute lymphoblastic leukemia.
Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children, and cure rates for adults remain dismal. Further, effective treatment strategies for relapsed/refractory ALL remain elusive. We previously uncovered that ALL cells are prone to apoptosis via endoplasmic reticulum (ER) stress/unfolded protein response (UPR)-mediated mechanisms. We investigated the antineoplastic activity of pevonedistat®, a novel NEDD8-activating enzyme inhibitor that targets E3 cullin-RING ligases (CRLs) dependent proteasomal protein degradation, in ALL. Herein, we report that pevonedistat induces apoptosis in ALL cells by dysregulating the translational machinery leading to induction of proteotoxic/ER stress and UPR-mediated cell death. Mechanistically, pevonedistat led to P-eIF2a dephosphorylation causing atypical proteotoxic/ER stress from failure to halt protein translation via the UPR and upregulation of mTOR/p70S6K. Additional studies revealed that pevonedistat re-balanced the homeostasis of pro- and anti-apoptotic proteins to favor cell death through altered expression and/or activity of Mcl-1, NOXA, and BIM, suggesting that pevonedistat has a "priming" effect on ALL by altering the apoptotic threshold through modulation of Mcl-1 activity. Further, we demonstrated that pevonedistat synergizes with selected anti-leukemic agents in vitro, and prolongs survival of NSG mice engrafted with ALL cells, lending support for the use of pevonedistat as part of a multi-agent approach.
Departments of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33101, United States; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, United States.
Gilles M
GM
Leclerc
The Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, FL 33101, United States.
Shuhua
S
Zheng
Departments of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33101, United States; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, United States.
Guy J
GJ
Leclerc
Departments of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33101, United States.
Joanna
J
DeSalvo
Medicine, University of Miami Miller School of Medicine, Miami, FL 33101, United States; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, United States.
Ronan T
RT
Swords
Departments of Pediatrics, University of Miami Miller School of Medicine, Miami, FL 33101, United States; Medicine, University of Miami Miller School of Medicine, Miami, FL 33101, United States; Biochemistry and Molecular Biology, University of Miami Miller School of Medicine, Miami, FL 33101, United States; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL 33101, United States. Electronic address: jbarredo@miami.edu.
Julio C
JC
Barredo
D000818:Animals; D000970:Antineoplastic Agents; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D003517:Cyclopentanes / Q000494:pharmacology* / Q000627:therapeutic use; D059865:Endoplasmic Reticulum Stress; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2 / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D000075687:NEDD8 Protein; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy*; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D014452:Ubiquitins / Q000037:antagonists & inhibitors*; D056811:Unfolded Protein Response / Q000187:drug effects*
D000970:Antineoplastic Agents; D003517:Cyclopentanes; D004791:Enzyme Inhibitors; D015852:Eukaryotic Initiation Factor-2; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D011743:Pyrimidines; D014452:Ubiquitins; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; C539933:pevonedistat
Combination targeted therapy; ER stress/UPR; Leukemia; MEK/ERK; NEDD8 conjugation pathway; NSG mice; Pevonedistat; Protein translation