Millennium Pharmaceuticals, Inc, Cambridge, MA 02139, USA.
Blood. 2010 Sep 2;116(9):1515-23. doi: 10.1182/blood-2010-03-272567. Epub 2010 Jun 4.
MLN4924 is a potent and selective small molecule NEDD8-activating enzyme (NAE) inhibitor. In most cancer cells tested, inhibition of NAE leads to induction of DNA rereplication, resulting in DNA damage and cell death. However, in preclinical models of activated B cell-like (ABC) diffuse large B-cell lymphoma (DLBCL), we show that MLN4924 induces an alternative mechanism of action. Treatment of ABC DLBCL cells with MLN4924 resulted in rapid accumulation of pIkappaBalpha, decrease in nuclear p65 content, reduction of nuclear factor-kappaB (NF-kappaB) transcriptional activity, and G(1) arrest, ultimately resulting in apoptosis induction, events consistent with potent NF-kappaB pathway inhibition. Treatment of germinal-center B cell-like (GCB) DLBCL cells resulted in an increase in cellular Cdt-1 and accumulation of cells in S-phase, consistent with cells undergoing DNA rereplication. In vivo administration of MLN4924 to mice bearing human xenograft tumors of ABC- and GCB-DLBCL blocked NAE pathway biomarkers and resulted in complete tumor growth inhibition. In primary human tumor models of ABC-DLBCL, MLN4924 treatment resulted in NF-kappaB pathway inhibition accompanied by tumor regressions. This work describes a novel mechanism of targeted NF-kappaB pathway modulation in DLBCL and provides strong rationale for clinical development of MLN4924 against NF-kappaB-dependent lymphomas.
MLN4924 是一种有效的、选择性的小分子 NEDD8-激活酶（NAE）抑制剂。在大多数测试的癌细胞中，NAE 的抑制会导致 DNA 再复制的诱导，从而导致 DNA 损伤和细胞死亡。然而，在激活 B 细胞样（ABC）弥漫性大 B 细胞淋巴瘤（DLBCL）的临床前模型中，我们表明 MLN4924 诱导了一种替代的作用机制。用 MLN4924 处理 ABC DLBCL 细胞会导致 pIkappaBalpha 的快速积累，核内 p65 含量减少，核因子-kappaB（NF-kappaB）转录活性降低，G1 期停滞，最终导致细胞凋亡诱导，这些事件与 NF-kappaB 途径的强烈抑制一致。用 MLN4924 处理生发中心 B 细胞样（GCB）DLBCL 细胞会导致细胞 Cdt-1 的增加和 S 期细胞的积累，这与细胞进行 DNA 再复制一致。在携带 ABC 和 GCB-DLBCL 人异种移植肿瘤的小鼠体内给予 MLN4924 会阻断 NAE 途径生物标志物，并导致完全的肿瘤生长抑制。在 ABC-DLBCL 的原发性人类肿瘤模型中，MLN4924 治疗导致 NF-kappaB 途径的抑制，并伴有肿瘤消退。这项工作描述了一种在 DLBCL 中靶向 NF-kappaB 途径调节的新机制，并为 MLN4924 针对 NF-kappaB 依赖性淋巴瘤的临床开发提供了强有力的理由。
