Activating NRF2^E79Q mutation alters the differentiation of human non-small cell lung cancer

The NRF2 signaling pathway promotes tumor initiation, progression and resistance to chemotherapy, radiation therapy and immune checkpoint inhibitors. The mechanisms underlying the biology of NRF2-active tumors are varied, and include altered cellular metabolism, a reductive shift in redox state, and immunosuppression. Here we determined the molecular and phenotypic impact of NRF2 activation on two human non-small cell lung cancer (NSCLC) cell models. Inducible expression of NRF2^E79Q, a common activating NRF2 mutation, in H358 lung adenocarcinoma (LUAD) cells altered cellular morphology and increased xenograft tumor growth in mice but not in 2D cell culture. In contrast, NRF2^E79Q expression in H596 lung adeno-squamous cell carcinoma altered cellular morphology, increased neuroendocrine marker gene expression, but did not impact tumor growth in 2D or in xenografts. Gene expression profiling revealed shared and unique NRF2 transcriptional programs between these models, some of which were shared in primary lung tumors. Collectively, our findings reveal context-dependent effects of NRF2 activation on the growth and differentiation-state of two human NSCLC models, supporting a new differentiation-centric mechanism of NRF2-driven tumor progression and therapeutic resistance.