KEAP1-NRF2 Pathway as a Novel Therapeutic Target for EGFR-Mutant Non-small Cell Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• The Kelch-like ECH-associated protein 1 (KEAP1)-nuclear factor erythroid-2-related factor 2 (NRF2) pathway regulates cellular defense against oxidative and metabolic stress.
• This pathway is implicated in resistance to chemotherapy and immunotherapy, but its role in oncogene-addicted tumors remains unclear.
• Investigating the NRF2 pathway's potential as a therapeutic target in EGFR-mutant non-small cell lung cancer (NSCLC).

Purpose of the Study:

• To determine if the NRF2 pathway is a viable therapeutic target in EGFR-mutant NSCLC.
• To evaluate the impact of NRF2 inhibition on cell death and tumor growth in EGFR-mutant NSCLC models.

Main Methods:

• Assessed baseline NRF2 expression in parental and gefitinib-resistant EGFR-mutant lung cancer cells.
• Utilized an NRF2 inhibitor to assess its effects on cell death in vitro and tumor growth in vivo using a xenograft mouse model.
• Performed RNA sequencing to analyze transcriptional changes following NRF2 inhibition.

Main Results:

• Enhanced NRF2 expression was observed in EGFR-mutant cells, particularly in gefitinib-resistant lines.
• NRF2 inhibition led to a dose-dependent decrease in NRF2 levels and induced significant cell death.
• Combined treatment with an NRF2 inhibitor and osimertinib improved cell death in vitro and suppressed tumor growth in vivo.
• RNA sequencing identified altered expression of multiple genes and signaling pathways upon NRF2 inhibition.

Conclusions:

• NRF2 inhibition effectively enhances cell death and inhibits tumor growth in TKI-resistant EGFR-mutant lung cancer.
• Targeting the NRF2 pathway presents a promising therapeutic strategy to overcome resistance to EGFR-TKIs in NSCLC.