Targeting the vulnerability to NAD + depletion in B-cell acute lymphoblastic leukemia

Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual i...

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Bibliographic Details
Published in:Leukemia 2018-03, Vol.32 (3), p.616-625
Main Authors: Takao, S, Chien, W, Madan, V, Lin, D-C, Ding, L-W, Sun, Q-Y, Mayakonda, A, Sudo, M, Xu, L, Chen, Y, Jiang, Y-Y, Gery, S, Lill, M, Park, E, Senapedis, W, Baloglu, E, Müschen, M, Koeffler, H P
Format: Article
Language:English
Subjects:
Abnormalities
Acute lymphoblastic leukemia
Acute lymphocytic leukemia
Adenine
Analysis
Animal models
Biosynthesis
Care and treatment
Cell growth
Depletion
Energy metabolism
Enzyme inhibitors
Health aspects
Inhibition
Inhibitors
Kinases
Leukemia
Lymphatic leukemia
Lymphocytes B
Metabolism
NAD
Nicotinamide
Nicotinamide adenine dinucleotide
Nicotinamide phosphoribosyltransferase
Nicotinic acid
p21-activated kinase
Patients
Phosphoribosyltransferase
Physiological aspects
Prognosis
Protein-serine/threonine kinase
Salvage
Supplements
Xenografts
Xenotransplantation
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Summary:Although substantial progress has been made in the treatment of B-cell acute lymphoblastic leukemia (B-ALL), the prognosis of patients with either refractory or relapsed B-ALL remains dismal. Novel therapeutic strategies are needed to improve the outcome of these patients. KPT-9274 is a novel dual inhibitor of p21-activated kinase 4 (PAK4) and nicotinamide phosphoribosyltransferase (NAMPT). PAK4 is a serine/threonine kinase that regulates a variety of fundamental cellular processes. NAMPT is a rate-limiting enzyme in the salvage biosynthesis pathway of nicotinamide adenine dinucleotide (NAD) that plays a vital role in energy metabolism. Here, we show that KPT-9274 strongly inhibits B-ALL cell growth regardless of cytogenetic abnormalities. We also demonstrate the potent in vivo efficacy and tolerability of KPT-9274 in a patient-derived xenograft murine model of B-ALL. Interestingly, although KPT-9274 is a dual PAK4/NAMPT inhibitor, B-ALL cell growth inhibition by KPT-9274 was largely abolished with nicotinic acid supplementation, indicating that the inhibitory effects on B-ALL cells are mainly exerted by NAD depletion through NAMPT inhibition. Moreover, we have found that the extreme susceptibility of B-ALL cells to NAMPT inhibition is related to the reduced cellular NAD reserve. NAD depletion may be a promising alternative approach to treating patients with B-ALL.
ISSN:0887-6924
1476-5551
DOI:10.1038/leu.2017.281