Division of Hematology, The Ohio State University, 455 OSUCCC, 410 West 12th Avenue, Columbus, OH, 43210, USA.
Department of Pathology, Stanford University, Palo Alto, CA, USA.
J Hematol Oncol. 2021 Jun 29;14(1):101. 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.
KPT-9274 是一种用于实体瘤和非霍奇金淋巴瘤的首创的第一类双 PAK4/NAMPT 抑制剂。它通过抑制 NAMPT 依赖性 NAD 产生，在急性髓系白血病 (AML) 亚型中显示出广泛的临床前疗效。NAMPT 是导致 NAD 产生的补救代谢途径中的限速酶。缺乏从头途径酶 NAPRT1 的肿瘤细胞依赖 NAMPT。在临床试验中，NAMPT 抑制剂的治疗导致剂量限制毒性。为了剖析毒性机制，用 KPT-9274 处理小鼠，并对其进行组织病理学和生物化学特征分析。KPT-9274 治疗导致性别依赖性的胃和肾损伤以及贫血。用 KPT-9274 治疗的雌性小鼠出现 EPO 缺乏症和相关的红细胞生成受损。KPT-9274 治疗抑制了 SIRT3 的表达，并同时上调了 IMCD3 细胞中的乙酰锰超氧化物歧化酶 (MnSOD)，为观察到的肾毒性提供了机制基础。重要的是，烟酰胺补充剂减轻了 KPT-9274 引起的肾损伤和 EPO 缺乏，而不影响其疗效。总之，我们的研究阐明了 KPT-9274 介导的毒性机制，并为开发提高这种重要的抗 AML 抑制剂耐受性的策略提供了思路。
