Extensive efforts have been conducted in the search for new targetable drivers of lung squamous cell carcinoma (LUSC); to date, however, candidates remain mostly unsuccessful. One of the oncogenic pathways frequently found to be active in LUSC is (NRF2 transcription factor), the levels of which are regulated by KEAP1. Mutations in or trigger NRF2 activation, an essential protector against reactive oxygen species (ROS). We hypothesized that the frequency of NRF2 activation in LUSC (∼35 %) may reflect a sensitivity of LUSC to ROS. Results from this study reveal that whereas tumors containing active forms of NRF2 were protected, ROS induction in wild-type / LUSC cells triggered ferroptosis. The mechanism of ROS action in normal-NRF2 LUSC cells involved transient NRF2 activation, -3p/-5p upregulation, and reduction of p85β and SETD5 levels. SETD5 levels reduction triggered pentose pathway gene levels increase to toxic values. Simultaneous depletion of p85β and SETD5 triggered LUSC cell death, while p85β and SETD5 overexpression rescued survival of ROS-treated normal-NRF2 LUSC cells. This shows that the cascade involving NRF2 > , > p85β and SETD5 is responsible for ROS-induced cell death in normal-NRF2 LUSC. Transient ROS-induced cell death is shown in 3D spheroids, patient-derived organoids, and in xenografts of wild-type LUSC cells, supporting the potential of acute local ROS induction as a therapeutic strategy for LUSC patients with normal-NRF2.

中文翻译：

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基于急性氧化应激诱导的野生型 NRF2/KEAP1 肺鳞状细胞癌的潜在治疗策略


人们在寻找肺鳞状细胞癌（LUSC）新的靶向驱动因素方面进行了广泛的努力；然而，迄今为止，候选人大多仍未成功。在 LUSC 中经常发现活跃的致癌途径之一是 (NRF2 转录因子)，其水平受 KEAP1 调节。突变或触发 NRF2 激活，NRF2 是对抗活性氧 (ROS) 的重要保护剂。我们假设 LUSC 中 NRF2 激活的频率（~35%）可能反映了 LUSC 对 ROS 的敏感性。这项研究的结果表明，虽然含有活性形式 NRF2 的肿瘤受到保护，但野生型/LUSC 细胞中 ROS 的诱导引发了铁死亡。正常 NRF2 LUSC 细胞中 ROS 作用的机制涉及瞬时 NRF2 激活、-3p/-5p 上调以及 p85β 和 SETD5 水平降低。 SETD5 水平降低引发戊糖途径基因水平增加至毒性值。同时耗尽 p85β 和 SETD5 会引发 LUSC 细胞死亡，而 p85β 和 SETD5 过表达则可挽救 ROS 处理的正常 NRF2 LUSC 细胞的存活。这表明涉及 NRF2 > 、> p85β 和 SETD5 的级联是正常 NRF2 LUSC 中 ROS 诱导的细胞死亡的原因。 3D 球体、患者来源的类器官和野生型 LUSC 细胞的异种移植物中显示了短暂的 ROS 诱导的细胞死亡，这支持了急性局部 ROS 诱导作为具有正常 NRF2 的 LUSC 患者的治疗策略的潜力。