Anti-tumor NAMPT inhibitor, KPT-9274, mediates gender-dependent murine anemia and nephrotoxicity by regulating SIRT3-mediated SOD deacetylation

• Published in: Journal of hematology and oncology Vol. 14; no. 1; pp. 101 - 5
• Main Authors: Mitchell, Shaneice, Zhang, Pu, Cannon, Matthew, Beaver, Larry, Lehman, Amy, Harrington, Bonnie, Sampath, Deepa, Byrd, John C., Lapalombella, Rosa
• Format: Journal Article
• Language: English
• Published: London BioMed Central 29.06.2021; BioMed Central Ltd; BMC
• Subjects: Acetylation - drug effects; Acrylamides - adverse effects; Acute myeloid leukemia; Aminopyridines - adverse effects; Anemia; Anemia - chemically induced; Anemia - etiology; Anemia - metabolism; Anemia - pathology; Animals; Antineoplastic Agents - adverse effects; Apoptosis; Blood; Cancer; Cancer Research; Clinical trials; Creatinine; Deacetylation; Drug dosages; Erythropoiesis; Erythropoiesis - drug effects; Erythropoietin; Female; Gender; Hematology; Humans; Kidney Diseases - chemically induced; Kidney Diseases - etiology; Kidney Diseases - metabolism; Kidney Diseases - pathology; Kidneys; Letter to the Editor; Leukemia; Male; Manganese; Medicine; Medicine & Public Health; Metabolic pathways; Mice; Myeloid leukemia; NAD; NAMPT; Niacin; Nicotinamide Phosphoribosyltransferase - antagonists & inhibitors; Nicotinamide Phosphoribosyltransferase - metabolism; Non-Hodgkin's lymphoma; Non-Hodgkin's lymphomas; Oncology; Sex Factors; Sirtuin 3 - metabolism; SOD; Solid tumors; Superoxide; Superoxide dismutase; Superoxide Dismutase - metabolism; Supplements; Toxicity; Tumor cells; Vitamin B; SOD; Erythropoietin; Niacin; Leukemia; NAMPT
• ISSN: 1756-8722; 1756-8722
• DOI: 10.1186/s13045-021-01107-0

KPT-9274 is a phase 1 first-in-class dual PAK4/NAMPT inhibitor for solid tumor and non-Hodgkin’s lymphoma. It demonstrates pre-clinical efficacy toward a broad spectrum of acute myeloid leukemia (AML) subtypes by inhibiting NAMPT-dependent NAD + production. NAMPT is the rate-limiting enzyme in the salvage metabolic pathway leading to NAD + generation. Tumor cells which are deficient in de novo pathway enzyme NAPRT1 are addicted to NAMPT. In clinical trials, treatment with NAMPT inhibitors resulted in dose-limiting toxicities. In order to dissect the mechanism of toxicity, mice were treated with KPT-9274 and resulting toxicities were characterized histopathologically and biochemically. KPT-9274 treatment caused gender-dependent stomach and kidney injuries and anemia. Female mice treated with KPT-9274 had EPO deficiency and associated impaired erythropoiesis. KPT-9274 treatment suppressed SIRT3 expression and concomitantly upregulated acetyl-manganese superoxide dismutase (MnSOD) in IMCD3 cells, providing a mechanistic basis for observed kidney toxicity. Importantly, niacin supplementation mitigated KPT-9274-caused kidney injury and EPO deficiency without affecting its efficacy. Altogether, our study delineated the mechanism of KPT-9274-mediated toxicity and sheds light onto developing strategies to improve the tolerability of this important anti-AML inhibitor.