Activating mutations in the KEAP1-NRF2 pathway are found in approximately 25% of lung tumors, where the hijacking of NRF2’s cytoprotective functions results in aggressive tumor growth, chemoresistance, and a poor prognosis for patients. There are currently no approved drugs which target aberrant NRF2 activation, which means that there is an urgent clinical need to target this orphan oncogenic pathway in human tumors. In this study, we used an isogenic pair of wild-type and Keap1 knockout cells to screen a range of chemotherapeutic and pathway-targeted anticancer drugs in order to identify compounds which display enhanced toxicity toward cells with high levels of Nrf2 activity. Through this approach, complemented by validation across a panel of eight human cancer cell lines from a range of different tissues, we identified the DNA-damaging agent mitomycin C to be significantly more toxic in cells with aberrant Nrf2 activation. Mechanistically, we found that the NRF2 target genes for cytochrome P450 reductase, NQO1, and enzymes in the pentose phosphate pathway are all responsible for the NRF2-dependent enhanced bioactivation of mitomycin C. As mitomycin C is already approved for clinical use, it represents as excellent drug repositioning candidate to target the currently untreatable NRF2 activation in human tumors.

中文翻译：

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NRF2 依赖性丝裂霉素 C 生物激活作为人类癌症中 KEAP1-NRF2 通路激活的新策略


大约 25% 的肺部肿瘤中发现了 KEAP1-NRF2 通路的激活突变，其中 NRF2 的细胞保护功能被劫持，导致肿瘤侵袭性生长、化疗耐药和患者预后不良。目前还没有针对异常 NRF2 激活的批准药物，这意味着临床迫切需要针对人类肿瘤中的这一孤儿致癌途径。在这项研究中，我们使用一对同基因的野生型细胞和 Keap1 敲除细胞来筛选一系列化疗和通路靶向抗癌药物，以确定对具有高水平 Nrf2 活性的细胞表现出增强毒性的化合物。通过这种方法，并通过对来自一系列不同组织的八种人类癌细胞系进行验证，我们发现 DNA 损伤剂丝裂霉素 C 在 Nrf2 激活异常的细胞中具有明显更高的毒性。从机制上讲，我们发现细胞色素 P450 还原酶、NQO1 和戊糖磷酸途径中的酶的 NRF2 靶基因均负责 NRF2 依赖性增强丝裂霉素 C 的生物活性。由于丝裂霉素 C 已被批准用于临床，因此它代表：优秀的药物重新定位候选药物，可针对人类肿瘤中目前无法治疗的 NRF2 激活。