To dissect the role of NRF2-active signaling in tumor development in a GEMM possessing mutations frequently found in human HNSCC, we generated two groups of mice—Tg(Krt14-creERTAM2); Trp53fl/fl; p16fl/fl; LSL-Nrf2WT/WT (CP mice) and Tg(Krt14-creERTAM2); Trp53fl/fl; p16fl/fl; LSL-Nrf2E79Q/WT (CPN mice). Here, KRT14 is linked to head and neck squamous cell carcinoma.