Imaging NRF2 activation in non-small cell lung cancer with positron emission tomography

Area of Science:

• Oncology
• Molecular Imaging
• Cancer Biology

Background:

• Mutations in the NRF2-KEAP1 pathway are prevalent in non-small cell lung cancer (NSCLC), contributing to therapeutic resistance and poor patient prognosis.
• Current diagnostic methods lack non-invasive approaches to identify NRF2 pathway activation in living subjects.

Purpose of the Study:

• To establish [18F]FSPG positron emission tomography as a non-invasive imaging biomarker for NRF2 activation in NSCLC.
• To investigate targeting the system xc- transporter as a therapeutic strategy in NSCLC.

Main Methods:

• Utilized [18F]FSPG positron emission tomography (PET) imaging in various NSCLC mouse models (orthotopic, patient-derived, genetically engineered).
• Analyzed NRF2-related gene expression signatures in a large cohort of NSCLC patients.
• Evaluated therapeutic targeting of system xc- using an antibody-drug conjugate.

Main Results:

• [18F]FSPG PET imaging demonstrated sensitive and specific detection of NRF2 activation across different NSCLC models.
• Identified a patient gene expression signature predictive of [18F]FSPG uptake, enabling potential patient preselection.
• Showcased system xc- as a metabolic vulnerability, with antibody-drug conjugate therapy leading to sustained tumor growth suppression.

Conclusions:

• [18F]FSPG serves as a valuable non-invasive imaging biomarker for predicting therapy resistance in NSCLC.
• System xc- represents a druggable target for therapeutic intervention in NSCLC.
• These findings support the clinical evaluation of [18F]FSPG imaging and system xc- targeted therapies for NSCLC.