临床前研究表明 MLN4924 是一种有前途的新型视网膜母细胞瘤疗法。,Cell Death Discovery

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临床前研究表明 MLN4924 是一种有前途的新型视网膜母细胞瘤疗法。
Cell Death Discovery ( IF 6.1 ) Pub Date : 2020-01-20 , DOI: 10.1038/s41420-020-0237-8
Arthur Aubry _{1,

2} , Tao Yu ₁ , Rod Bremner _{1,

2,

3}

Affiliation

胎儿视网膜中的 RB1 缺失 (RB1 null ) 或 MYCN 扩增 (MYCN amp ) 会导致视网膜母细胞瘤。SKP2 缺失会杀死 RB1 无效细胞，但小分子 SKP2 抑制剂在治疗上仍未得到探索。SKP2 在 MYCN amp 视网膜母细胞瘤中是否具有合成致死性尚不清楚。SKP2 是两个 Cullin-RING 连接酶复合物（CRL1SKP2/SCFSKP2 和 CRL4SKP2）的底物识别组件，这是一个多蛋白 E3 泛素连接酶家族。Cullin neddylation 和 CRL 激活需要 NEDD8 激活酶 (NAE)。在这里，我们证明 NAE 抑制剂 Pevonedistat (MLN4924) 能有效抑制 RB1 null 和 MYCN amp 肿瘤。玻璃体内 MLN4924 可抑制多个人类异种移植物，EC80 范围为 20 ng 至 3.5 μg。最大耐受剂量 (MTD) 为 10-30 μg，突出了有利的治疗窗口。Cullin neddylation 的抑制在所有情况下都是相似的，但细胞效应的范围从导致细胞凋亡的 G1 停滞到导致核内复制的 G2/M 停滞。然而，即使在不太敏感的细胞系中（EC50 ≈ 1 μM），长时间暴露也是致命的或诱导持续的细胞抑制。从机制上讲，消耗任何单个 Cullin 并不能完全重现药物表型，但对 SKP2 缺失的敏感性与药物的敏感性相关。因此，玻璃体内 MLN4924 是一种有前途的新型视网膜母细胞瘤疗法，模仿消除 SKP2 复合物的癌症特异性致死率。

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Preclinical studies reveal MLN4924 is a promising new retinoblastoma therapy.

RB1 loss (RB1 null ) or MYCN amplification (MYCN amp ) in fetal human retina causes retinoblastoma. SKP2 loss kills RB1 null cells, but small molecule SKP2 inhibitors remain unexplored therapeutically. Whether SKP2 is synthetic lethal in MYCN amp retinoblastoma is unclear. SKP2 is the substrate recognition component of two Cullin-RING Ligase complexes (CRL1SKP2/SCFSKP2, and CRL4SKP2), a family of multiprotein E3 ubiquitin ligases. NEDD8 activating enzyme (NAE) is required for Cullin neddylation and thus CRL activation. Here, we show that the NAE inhibitor, Pevonedistat (MLN4924), potently inhibits RB1 null and MYCN amp tumors. Intravitreal MLN4924 suppressed multiple human xenografts with EC80s from 20 ng to 3.5 μg. Maximum tolerated dose (MTD) was 10-30 μg, highlighting a favorable therapeutic window. Inhibition of Cullin neddylation was similar in all cases, but cellular effects ranged from G1 arrest with apoptosis to G2/M arrest with endoreplication. However, even in less sensitive lines (EC50 ≈ 1 μM), prolonged exposure was lethal or induced persistent cytostasis. Mechanistically, depleting any single Cullin did not fully recapitulate drug phenotypes, but sensitivity to SKP2 loss correlated with that of drug. Thus, intravitreal MLN4924 is a promising new retinoblastoma therapy, mimicking the cancer-specific lethality of eliminating SKP2 complexes.

更新日期：2020-01-20

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