Department of Radiation and Medical Oncology, Hubei Key Laboratory of Tumor Biological Behaviors, Hubei Cancer Clinical Study Center, Zhongnan Hospital of Wuhan University, 430071, Wuhan, China.
Medical Research Institute, Wuhan University, 430071, Wuhan, China.
Oncogene. 2019 Oct;38(41):6737-6751. doi: 10.1038/s41388-019-0912-5. Epub 2019 Aug 12.
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-eIF2α-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.
MYCN 扩增预测神经母细胞瘤预后不良和对治疗的耐药性。然而，由于其“不可成药”的蛋白质结构，直接抑制 MYC 的药物策略仍然不成功。我们在此使用临床批准的治疗试剂针对 MYCN 扩增的神经母细胞瘤开发了一种合成致死筛选。我们使用了 938 种 FDA 批准药物的文库进行高通量筛选，以寻找在 MYC 驱动的神经母细胞瘤细胞中产生合成致死效应的候选药物。蛋白酶体抑制剂是 FDA 批准用于多发性骨髓瘤一线治疗的药物，是产生 MYC 介导的合成致死性的最佳选择。蛋白酶体抑制在 MYC 转化细胞中激活 PERK-eIF2α-ATF4 轴，并通过 ATF4 依赖性 NOXA 和 TRIB3 诱导诱导 BAX 介导的细胞凋亡。组合筛选显示蛋白酶体抑制剂硼替佐米（BTZ）和组蛋白去乙酰化酶（HDAC）抑制剂伏立诺他（SAHA）协同诱导部分通过 BAX 的协同激活导致明显的细胞死亡。这种组合在体内显著抑制肿瘤生长，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，这项具有体内验证的 FDA 批准药物筛选为在 MYC 驱动的神经母细胞瘤患者中单独或联合使用硼替佐米和伏立诺他进行临床评估提供了依据。
