Distinct Nrf2 Signaling Thresholds Mediate Lung Tumor Initiation and Progression

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Mutations in the KEAP1-NRF2 pathway are prevalent in non-small cell lung cancer (NSCLC), correlating with therapeutic resistance and poor prognosis.
• The KEAP1-NRF2 pathway regulates cellular defense mechanisms and is frequently dysregulated in various cancers.

Purpose of the Study:

• To investigate the precise role of KEAP1 and NRF2 mutations in NSCLC initiation and progression using murine models.
• To determine the context-dependent and threshold-dependent effects of NRF2 activation in lung tumorigenesis.

Main Methods:

• Development of murine alleles mimicking human KEAP1 and NRF2 mutations found in NSCLC.
• Comprehensive analysis of tumor initiation and progression in genetically engineered mouse models.
• Assessment of NRF2 overexpression effects on KEAP1-mutant human NSCLC cell lines.

Main Results:

• Constitutive NRF2 activation alone or with p53/LKB1 loss did not induce tumorigenesis.
• NRF2 activation with KrasG12D/+ promoted early tumor initiation but inhibited progression to advanced-grade tumors.
• NRF2 deletion reversed the inhibitory effect on advanced tumor progression.
• NRF2 overexpression was detrimental to the proliferation and viability of KEAP1-mutant NSCLC cells.

Conclusions:

• NRF2 stabilization has context-dependent and threshold-dependent roles in lung tumorigenesis, promoting initiation but blocking progression.
• The KEAP1-NRF2 pathway's activity threshold is critical for its function in different stages of lung cancer development.