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

Leukemia
S TakaoH Phillip Koeffler

Abstract

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 inhi...Continue Reading

References

Apr 9, 2004·The New England Journal of Medicine·Ching-Hon PuiJames R Downing
May 30, 2006·Biochemical and Biophysical Research Communications·Pinar AksoyEduardo N Chini
Oct 13, 2006·Blood·Adele K FieldingEastern Cooperative Oncology Group
Jul 23, 2008·Molecular Cancer Research : MCR·Yingying LiuAudrey Minden
Dec 26, 2008·Trends in Endocrinology and Metabolism : TEM·Antje GartenWieland Kiess
Mar 7, 1927·The Journal of General Physiology·O WarburgE Negelein
Jul 8, 2010·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Renato BassanAlessandro Rambaldi
Mar 8, 2011·Cell·Douglas Hanahan, Robert A Weinberg
Aug 7, 2012·Frontiers in Oncology·Ming YangJulie Adam
Sep 13, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Claudia C S ChiniEduardo N Chini
Oct 8, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·David S ShamesLisa D Belmont
Feb 8, 2014·Nature Reviews. Cancer·Maria RaduJonathan Chernoff
Aug 31, 2014·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Iris GehrkeVersha Banerji
Feb 25, 2015·Pharmacology & Therapeutics·Deepak SampathPeter S Dragovich
Dec 19, 2015·Cancer Cell·Kensuke TateishiDaniel P Cahill
Jul 9, 2016·Molecular Cancer Therapeutics·Omran Abu AboudRobert H Weiss

Citations

Jan 17, 2019·Anti-cancer Agents in Medicinal Chemistry·Yingze WeiXiaoxia Jin
Dec 4, 2019·Current Opinion in Pediatrics·Sameer H Issaq, Christine M Heske
Sep 19, 2019·Journal of the National Cancer Institute. Monographs·Etan OrgelSteven D Mittelman
Jan 2, 2021·Signal Transduction and Targeted Therapy·Lola E Navas, Amancio Carnero
Oct 2, 2020·Molecular Therapy : the Journal of the American Society of Gene Therapy·Jasper Edgar NeggersDirk Daelemans
Jan 10, 2020·Experimental Gerontology·Nady Braidy, Yue Liu

Related Concepts