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：

---

丝裂霉素C的依赖NRF2的生物激活作为靶向人类癌症中KEAP1-NRF2途径激活的新策略

在大约25％的肺部肿瘤中发现了KEAP1-NRF2途径中的活化突变，其中劫持NRF2的细胞保护功能会导致侵袭性肿瘤生长，化学耐药性和患者预后不良。当前尚无针对NRF2异常激活的靶向药物，这意味着迫切需要在人类肿瘤中靶向这种孤立的致癌途径。在这项研究中，我们使用了一对同基因的野生型和Keap1基因敲除细胞来筛选一系列化学疗法和靶向通路的抗癌药物，以鉴定对高水平Nrf2活性的细胞具有增强毒性的化合物。通过这种方法，再辅以一系列来自不同组织的八种人类癌细胞系的验证，我们发现DNA破坏剂丝裂霉素C在异常Nrf2激活的细胞中具有更大的毒性。从机理上讲，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靶基因均与丝裂霉素C的NRF2依赖性增强生物激活有关。由于丝裂霉素C已获批准用于临床，因此代表靶向人肿瘤中目前不可治愈的NRF2激活的优秀药物重新定位候选者。