Dysfunctional KEAP1-NRF2 interaction in non-small-cell lung cancer

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Nuclear factor erythroid-2 related factor 2 (NRF2) is a transcription factor that protects normal cells from oxidative stress.
• Kelch-like ECH-associated protein 1 (KEAP1) normally inhibits NRF2 activity.
• Tumor cells can develop resistance to chemotherapy by upregulating antioxidant and detoxification pathways.

Purpose of the Study:

• To investigate the frequency and functional impact of KEAP1 genetic alterations in lung cancer.
• To determine if KEAP1 inactivation contributes to chemoresistance in non-small cell lung cancer (NSCLC).

Main Methods:

• Systematic analysis of the KEAP1 genomic locus in NSCLC cell lines and patient tumors.
• Sequencing of KEAP1 to identify somatic mutations.
• Evaluation of loss of heterozygosity at the KEAP1 locus (19p13.2).

Main Results:

• Somatic mutations and loss of heterozygosity in KEAP1 were frequently observed in NSCLC.
• Mutations occurred in functionally important domains of KEAP1, likely abolishing its repressor activity.
• KEAP1 inactivation led to increased nuclear NRF2 accumulation and enhanced expression of NRF2-target genes.

Conclusions:

• Biallelic inactivation of KEAP1 is a common genetic event in NSCLC.
• KEAP1 loss activates the NRF2 pathway, conferring a survival advantage to cancer cells against chemotherapeutic agents.