Abstract NFE2-related factor 2 (Nrf2) is a transcription factor that regulates more than 500 genes in human cells to protect them from oxidative damage. Somatic mutations in NRF2 resulting in constitutively Nrf2 signaling have been implicated as driver mutations in cancer, especially lung cancer. However, the mechanisms by which NRF2 activating mutations drive tumor development remains unresolved. Therefore, we used a novel genetically engineered mouse model (GEMM), LSL-Nrf2E79Q/+, to understand the role of this activating mutation (one of the most common mutations found in human tumors) in the development of lung tumors. We compared tumor development in two groups of mice: p53fl/fl; p16fl/fl; LSL-Nrf2+/+ (WT, n=38) and p53fl/fl; p16fl/fl; Nrf2E79Q/+ (Het, n=37). We used intranasal instillation of Adenoviral Cre at 6-8 weeks of age to activate the Nrf2E79Q allele and inactivate p53 and p16. Among other tumors, lung tumors were the most common tumors that were found in the GEMM, with major subtypes of lung squamous dysplasia (LSD: pre-malignant lesions of lung squamous cell carcinoma (LSCC)) and lung adenocarcinoma (LADC). Additionally, Het mice showed significantly higher LSD (30%) compared to WT mice (11%) implicating Nrf2E79Q/+ in LSD initiation. However, no significant difference in LADC was observed in Het mice compared to WT mice. Immunohistochemistry (IHC) including Nrf2, TTF1, CK7 and p63 was used to differentiate lung tumors. LADC of WT and Het mice showed negative Nrf2 staining despite the presence of the recombined Nrf2E79Q/+ allele in the Het tumors. However, LSDs developed by Het mice showed positive Nrf2 staining, while those in WT mice were negative, suggesting the mutant Nrf2 increased the frequency of LSDs. LADC of both groups was positive for TTF1 (A primary-non small lung cancer marker, mostly LADC) and CK7 (Cytokeratin7: a marker of epithelial cells). However, LSD lesions were also positive for TTF1. No p63 (a marker of LSCC) stain was shown for LADC of both groups; while p63 was negative to mildly positive in the case of LSD. Results of this study appear consistent with TCGA results where LADC predominantly contained Keap1 loss, while Nrf2 mutations frequently appeared in LSCC. This is the first study to show that a common activating mutation of Nrf2 promotes initiation of LSD that could further develop into LSCC. Citation Format: Samera H. Hamad, Stephanie Montgomery, Brittany Bowman, Ryan Murphy, Ben Major, Bernard Weissman. Activation of the Nrf2E79Q mutation in mouse lung accelerate development of lung squamous dysplasia [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1628.