Data from Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

Abstract

<div>Abstract<p>Mutations in the KEAP1–NRF2 (Kelch-like ECH-associated protein 1–nuclear factor-erythroid 2 p45-related factor 2) pathway occur in up to a third of non–small cell lung cancer (NSCLC) cases and often confer resistance to therapy and poor outcomes. Here, we developed murine alleles of the <i>KEAP1</i> and <i>NRF2</i> mutations found in human NSCLC and comprehensively interrogated their impact on tumor initiation and progression. Chronic NRF2 stabilization by <i>Keap1</i> or <i>Nrf2</i> mutation was not sufficient to induce tumorigenesis, even in the absence of tumor suppressors, p53 or LKB1. When combined with <i>Kras</i><sup>G12D/+</sup>, constitutive NRF2 activation promoted lung tumor initiation and early progression of hyperplasia to low-grade tumors but impaired their progression to advanced-grade tumors, which was reversed by NRF2 deletion. Finally, NRF2 overexpression in KEAP1 mutant human NSCLC cell lines was detrimental to cell proliferation, viability, and anchorage-independent colony formation. Collectively, these results establish the context-dependence and activity threshold for NRF2 during the lung tumorigenic process.</p>Significance:<p>Stabilization of the transcription factor NRF2 promotes oncogene-driven tumor initiation but blocks tumor progression, indicating distinct, threshold-dependent effects of the KEAP1/NRF2 pathway in different stages of lung tumorigenesis.</p></div>