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.

中文翻译：

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格尔德霉素衍生的HSP90抑制剂与NRF2合成致死。

KEAP1-NRF2中的激活突变经常在肺，食道和肝脏的肿瘤中发现，这些突变与侵袭性生长，对癌症疗法的抵抗力以及总体存活率低有关。尽管NRF2是经验证的肿瘤发生和化学治疗耐药性驱动因素，但目前尚无批准的药物可以抑制其活性。因此，迫切需要鉴定NRF2选择性癌症疗法的临床。为此，我们开发了一种基于荧光标记的等基因野生型和Keap1基因敲除细胞系的新型合成致死试验，以筛选能够以NRF2依赖性方式选择性杀死细胞的化合物。通过这种方法，我们基于格尔德霉素支架鉴定了三种化合物，它们显示出与NRF2的合成致死性。机械上，我们显示NRF2靶基因的产物将含醌的格尔德霉素化合物代谢为更有效的HSP90抑制剂，从而增强了它们的细胞毒性，同时限制了具有异常NRF2活性的细胞的合成致死作用。由于这三种衍生自格尔德霉素的化合物均已用于临床试验，它们代表了药物重新定位的理想候选药物，以靶向目前癌症中无法治愈的NRF2活性。