Targeting NEDDylation for Therapeutic Gain of Acute Lymphoblastic Leukemia

Nova Southeastern University, Davie, Florida, USA

Objective. This comprehensive study aims to uncover the therapeutic potential of inhibiting the novel NEDDylation Activating Enzyme (NAE) using pevonedistat for the therapeutic gain of ALL treatment. Background. Acute lymphoblastic leukemia (ALL) is the leading cause of cancer-related death in children. Previous data from our lab and others showed that ALL cells are sensitive towards endoplasmic reticulum (ER) stress/unfolded protein response (UPR) inducers. In search for novel strategies to target the ER stress/UPR pathways in ALL, we identified the novel NAE inhibitor pevonedistat can efficiently kill ALL cells in vitro and in vivo. Mechanistic studies indicated that hyper-activation of cytotoxic ER stress/UPR was mainly responsible for pevonedistat-induced ALL cell death. We also identified aberrant activation MEK/ERK signaling in pevonedistat-treated ALL cells as a compensatory pro-survival pathway, co-targeting of which will induce synergistic anti-ALL effects. Methods. Molecular biology techniques were used in this study. NSG bioluminescent mouse model was developed to evaluate the in vivo efficacy of pevonedistat. Results. We found that pevonedistat treatment induced concomitant activation of p-mTOR (Ser2448) pathway and de-phosphorylation/activation of p-eIF2alpha (Ser51) which will dysregulate the protein homeostasis in ALL cells, triggering proteotoxic ER stress. Combinational treatment of pevonedistat with clinical-in-use drugs showed potent synergistic drug-drug interactions. Further study identified Ca2+-dependent activation of MEK/ERK signaling activation in pevonedistat-treated ALL cells as a compensatory pro-survival mechanism. This study leads to the initiation of the Phase I clinical trial of pevonedistat for refractory/relapsed pediatric ALL treatment (ClinicalTrials.gov Identifier: NCT03349281).