NRF2 Activation Promotes Aggressive Lung Cancer and Associates with Poor Clinical Outcomes.

Area of Science:

• Oncology
• Molecular Biology
• Genomics

Background:

• Genomic alterations in KEAP1 and NFE2L2 lead to NRF2 pathway stabilization in lung cancers.
• NRF2 activation is prevalent in lung adenocarcinoma and lung squamous cell carcinoma, often co-occurring with STK11 loss and KRAS mutations.
• The precise impact of NRF2 activation on tumor progression and patient outcomes remains incompletely understood.

Purpose of the Study:

• To investigate the role of NRF2 activation in lung cancer development and progression using in vivo models.
• To analyze the impact of NRF2 activation, STK11 loss, and KRAS activation on patient outcomes and immune contexture in immunotherapy trials.

Main Methods:

• Development of genetically engineered mouse models to simulate NRF2 activation, STK11 loss, and KRAS activation.
• Derivation of a NRF2 activation signature from human non-small cell lung tumors.
• Analysis of patient data from the OAK and IMpower131 immunotherapy trials using the NRF2 signature.

Main Results:

• In vivo modeling demonstrated that NRF2 activation promotes rapid-onset lung carcinomas and reduces redox stress in KRAS-mutant, STK11-null tumors.
• A NRF2 activation signature was negatively prognostic in patients with nonsquamous tumors, independent of STK11 loss.
• Patients with lung squamous cell carcinoma and a low NRF2 signature showed improved survival with anti-PD-L1 treatment.

Conclusions:

• NRF2 activation acts as a critical oncogenic driver, collaborating with STK11 loss and KRAS activation to promote aggressive lung adenocarcinoma.
• Genomic events, including NRF2 activation, significantly alter the tumor immune microenvironment, potentially influencing treatment responses.
• Patients with NRF2-activated lung tumors (both nonsquamous and squamous) exhibit poor prognosis and diminished response to anti-PD-L1 therapy.