Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan
Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Japan.
Mol Cell Biol. 2020 Oct 26;40(22). doi: 10.1128/MCB.00377-20.
Activating mutations in KEAP1-NRF2 are frequently found in tumors of the lung, esophagus, and liver, where they are associated with aggressive growth, resistance to cancer therapies, and low overall survival. Despite the fact that NRF2 is a validated driver of tumorigenesis and chemotherapeutic resistance, there are currently no approved drugs which can inhibit its activity. Therefore, there is an urgent clinical need to identify NRF2-selective cancer therapies. To this end, we developed a novel synthetic lethal assay, based on fluorescently labeled isogenic wild-type and Keap1 knockout cell lines, in order to screen for compounds which selectively kill cells in an NRF2-dependent manner. Through this approach, we identified three compounds based on the geldanamycin scaffold which display synthetic lethality with NRF2. Mechanistically, we show that products of NRF2 target genes metabolize the quinone-containing geldanamycin compounds into more potent HSP90 inhibitors, which enhances their cytotoxicity while simultaneously restricting the synthetic lethal effect to cells with aberrant NRF2 activity. As all three of the geldanamycin-derived compounds have been used in clinical trials, they represent ideal candidates for drug repositioning to target the currently untreatable NRF2 activity in cancer.
KEAP1-NRF2 中的激活突变在肺癌、食管癌和肝癌的肿瘤中经常被发现，它们与侵袭性生长、癌症治疗耐药和整体生存率低有关。尽管 NRF2 是肿瘤发生和化疗耐药的已验证驱动因素，但目前尚无可抑制其活性的批准药物。因此，迫切需要识别 NRF2 选择性癌症疗法。为此，我们开发了一种基于荧光标记的同基因野生型和 Keap1 敲除细胞系的新型合成致死测定法，以筛选以 NRF2 依赖性方式选择性杀死细胞的化合物。通过这种方法，我们确定了三种基于金纳米棒骨架的化合物，它们与 NRF2 具有合成致死性。从机制上讲，我们表明 NRF2 靶基因的产物将含有醌的金纳米棒化合物代谢成更有效的 HSP90 抑制剂，这增强了它们的细胞毒性，同时将合成致死作用限制在具有异常 NRF2 活性的细胞中。由于所有三种金纳米棒衍生化合物都已在临床试验中使用，因此它们是重新定位药物以靶向目前无法治疗的癌症中 NRF2 活性的理想候选物。
