Lung cancer is responsible for the most cancer-related deaths worldwide. Within the most prominent histological subtype, non-small cell lung cancer (NSCLC), there is an unmet clinical need: lung adenocarcinomas (ADCs) driven by mutant KRAS. Within this subset of tumors, KRAS mutations co-occur with mutations in tumor suppressor genes including TP53 and the redox regulator KEAP1. KEAP1 is the negative regulator of transcription factor NRF2, which directs the antioxidant response and multiple facets of metabolism. In NSCLC, alterations in the KEAP1-NRF2 circuit result in constitutive NRF2 activation and are often associated with resistance to therapy and poor outcomes in patients. While NRF2 hyperactivation has been associated with tumor progression, our lab's recent findings suggest that this may be context-dependent, and that too much NRF2 activation may be detrimental. To study the role of NRF2 hyperactivation on tumor progression, we have utilized KRAS mutant genetically engineered mouse models of NSCLC harboring TP53 deletion. These studies are based on our lab's finding that the homozygous KEAP1R554Q loss-of-function mutation decreases tumor size in a Kras mutant, Trp53-deficient (KP) lung ADC model (Kang et al. 2019 eLife). In parallel to these studies, we have also developed a conditional murine allele of the NRF2D29H mutation found in human NSCLC to serve as a secondary model of NRF2 hyperactivation in the KP mouse (KPN). Consistent with our homozygous KEAP1 mutant model (KPKK), we found that KPN mice demonstrated constitutive NRF2 activation, as observed by increased immunohistochemical staining of canonical NRF2 target, NQO1. This degree of NRF2 activation in KPN mice was slightly lower than that of KPKK mice, suggesting that the KPN mouse is an intermediate model of NRF2 activation. Supportingly, we also found that KPN mice had decreased tumor burden, although not to the same extent as KPKK mice. Interestingly, our heterozygous KEAP1 mutant model (KPK) demonstrates only modest NRF2 activation but did not exhibit decreased tumor burden. Importantly, analyses of tumor number suggested that KPKK and KPN tumors are impaired in tumor progression, rather than initiation. KPKK and KPN tumors also exhibited lower proliferative indices when compared to KP mice, in correspondence with their reduced tumor burden. Collectively, these results suggest that there may be a threshold for NRF2 activation to block tumor progression in the KP model. Current studies are focused on determining whether this impediment to tumor burden is NRF2-dependent, and what NRF2-dependent mechanisms may impair tumor progression. Importantly, these studies may help identify whether a threshold for NRF2 hyperactivation to promote or block tumor progression exists, and if this can be therapeutically exploited in patients with KRAS mutant, TP53-deficient lung tumors. Citation Format: Janine M. DeBlasi, Aimee Falzone, Gina M. DeNicola. Does a threshold exist for NRF2 hyperactivation to block tumor progression in KRAS mutant, TP53-deficient NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2507.