# Activating NRF2E79Q mutation alters the differentiation of human non-small cell lung cancer

## TL;DR

This study shows that activating a specific NRF2 mutation changes the growth and differentiation of human lung cancer cells in different ways.

## Contribution

The study reveals context-dependent effects of NRF2E79Q mutation on NSCLC cell differentiation and tumor growth.

## Key findings

- NRF2E79Q expression altered morphology and increased tumor growth in H358 LUAD cells in xenografts.
- NRF2E79Q increased neuroendocrine markers in H596 cells without affecting tumor growth.
- Shared and unique NRF2 transcriptional programs were identified between models and primary tumors.

## Abstract

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 NRF2E79Q, 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, NRF2E79Q 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 role for NRF2 activation in altering the differentiation of human NSCLC during tumor progression.