KEAP1-NRF2途径的突变在高达三分之一的非小细胞肺癌(NSCLC)患者中发生，并经常导致抗治疗和不良结局。在此，我们开发了人类NSCLC中发现的KEAP1和NRF2突变的小鼠等位基因，并全面研究了它们对肿瘤起始和进展的影响。通过Keap1或Nrf2突变引起长期的NRF2稳定并不足以诱导肿瘤发生，即使缺乏肿瘤抑制因子p53或LKB1。与KrasG12D / +组合时，恒定的NRF2激活促进了肺部肿瘤的起始和初期增生的进展到低级别的肿瘤，但妨碍了它们进展到高级别的肿瘤，NRF2的缺失可以逆转此现象。最后，在KEAP1突变的人类NSCLC细胞系中NRF2的过表达对细胞增殖、存活和无锚定的胚胎成像形成是有害的。总之，这些结果建立了肺肿瘤发生过程中NRF2的情境依赖性和活性阈值。

Mutations in the KEAP1-NRF2 pathway occur in up to a third of non-small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the KEAP1 and NRF2 mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by Keap1 or Nrf2 mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors p53 or LKB1. When combined with KrasG12D/+, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.