FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma
FDA-approved drug screen identifies proteasome as a synthetic lethal target in MYC-driven neuroblastoma
复制标题
DOI：
10.1038/s41388-019-0912-5
复制
发表时间：
2019-10-10
期刊：
影响因子：
8
通讯作者：
Liu, Hudan
中科院分区：
文献类型：
--
作者：
Wang, Jingchao;Jiang, Jue;Liu, Hudan
神经母细胞瘤中MYCN扩增预示预后不良和对治疗的抵抗。然而，直接抑制MYC的药理学策略仍然不成功，这是由于其“不可药用”的蛋白质结构。我们在此开发了一种使用临床批准的治疗试剂针对MYCN扩增的神经母细胞瘤的合成致死筛选。我们从938种FDA批准的药物库中进行了高通量筛选，以寻找在MYC驱动的神经母细胞瘤细胞中引起合成致死作用的候选药物。FDA批准用于多发性骨髓瘤一线治疗的蛋白酶体抑制剂成为引发MYC介导的合成致死性的热门药物。蛋白酶体抑制激活MYC转化细胞中的PERK-eIF 2 α-ATF 4轴，并通过ATF 4依赖性NOXA和TRIB 3诱导诱导BAX介导的细胞凋亡。组合筛选揭示了蛋白酶体抑制剂硼替佐米（BTZ）和组蛋白脱乙酰酶（HDAC）抑制剂伏立诺他（SAHA）部分地通过BAX的协同激活而一致地诱导显著的细胞死亡。这种组合在体内引起显著的肿瘤抑制，支持双重蛋白酶体/HDAC抑制作为MYC驱动的癌症的潜在治疗方法。因此，FDA批准的具有体内验证的药物筛选为单独或与伏立诺他联合使用硼替佐米在MYC驱动的神经母细胞瘤患者中的临床评价提供了依据。
MYCN amplification in neuroblastoma predicts poor prognosis and resistance to therapy. Yet pharmacological strategies of direct MYC inhibition remain unsuccessful due to its "undruggable" protein structure. We herein developed a synthetic lethal screen against MYCN-amplified neuroblastomas using clinically approved therapeutic reagents. We performed a high-throughput screen, from a library of 938 FDA-approved drugs, for candidates that elicit synthetic lethal effects in MYC-driven neuroblastoma cells. The proteasome inhibitors, which are FDA approved for the first-line treatment of multiple myeloma, emerge as top hits to elicit MYC-mediated synthetic lethality. Proteasome inhibition activates the PERK-eIF2 alpha-ATF4 axis in MYC-transformed cells and induces BAX-mediated apoptosis through ATF4-dependent NOXA and TRIB3 induction. A combination screen reveals the proteasome inhibitor bortezomib (BTZ) and the histone deacetylase (HDAC) inhibitor vorinostat (SAHA) concertedly induce dramatic cell death in part through synergistic activation of BAX. This combination causes marked tumor suppression in vivo, supporting dual proteasome/HDAC inhibition as a potential therapeutic approach for MYC-driven cancers. This FDA-approved drug screen with in vivo validation thus provides a rationale for clinical evaluation of bortezomib, alone or in combination with vorinostat, in MYC-driven neuroblastoma patients.