Activation Of Nrf2 Signaling Accelerates Development Of Small Cell Lung Cancer In Mice.

Abstract Activating mutations in NRF2 frequently occur in human lung cancers, especially the E79Q mutation. However, how the activating mutation contributes to lung tumor development is not well understood. We used a new genetically engineered mouse model (GEMM), LSL-Nrf2E79Q/+ with Cre-inducible expression of this mutation within the endogenous Nrf2 locus, to understand its contribution to lung tumor development. We compared tumor development in p53fl/fl;p16fl/fl;LSL-Nrf2+/+ (WT) versus p53fl/fl;p16fl/fl;Nrf2E79Q/+ (Het) mice after intranasal instillation of Adenoviral Cre. While we did not observe a significant difference in lung adenocarcinoma (LUAC) between the Het and WT mice, the Het mice showed significantly higher frequencies of bronchial neuroendocrine tumors that resembled small cell lung carcinomas (SCLC) compared to WT. Additionally, the latency of SCLC lesions was lower in Het mice compared to WT. Surprisingly, LUACs in both groups were negative for NRF2 by IHC labeling despite recombination of the mutant Nrf2 allele. While all lesions in the WT and Het mice displayed positive ASCL1 and CGRp (NE markers) IHC labeling, only the SCLCs in Het mice expressed NRF2. This is the first study showing activation of Nrf2E79Q mutation drives development of small cell lung carcinomas. Interestingly, our data also suggest that the E79Q NRF2 activating mutation may inhibit the progression of LUAD. Citation Format: Samera Hamad, Stephanie Montgomery, Brittany Bowman, Ryan Murphy, Scott Randell, Trudy Oliver, D. Neil Hayes, M. Ben Major, Bernard Weissman. Activation of NRF2 signaling accelerates development of small cell lung cancer in mice [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 2939.