Journal Article

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

Madan, V, Senapedis, W, Gery, S, Takao, S, Sudo, M, Chen, Y, Lin, D-c, Mayakonda, A, Koeffler, H P, Ding, L-w, Chien, W, Sun, Q-y, Xu, L, Lill, M, Park, E, Baloglu, E, Müschen, M, Jiang, Y-y

2018

Overview

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.

• Publisher: Nature Publishing Group
• Subject: Abnormalities / Acute lymphoblastic leukemia / Adenine / Animal models / Biosynthesis / Cell growth / Depletion / Energy metabolism / Enzyme inhibitors / Inhibition / Inhibitors / Kinases / Leukemia / Lymphatic leukemia / Lymphocytes B / Metabolism / NAD / Nicotinamide / Nicotinamide adenine dinucleotide / Nicotinamide phosphoribosyltransferase / Nicotinic acid / p21-activated kinase / Patients / Phosphoribosyltransferase / Protein-serine/threonine kinase / Salvage / Supplements / Xenografts / Xenotransplantation