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

PURPOSE

Stabilization of the transcription factor NRF2 through genomic alterations in and occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, loss often co-occurs with loss and -activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined.

EXPERIMENTAL DESIGN

We model NRF2 activation, loss, and activation using novel genetically engineered mouse models. Furthermore, we derive a NRF2 activation signature from human non-small cell lung tumors that we use to dissect how these genomic events impact outcomes and immune contexture of participants in the OAK and IMpower131 immunotherapy trials.

RESULTS

Our data reveal roles for NRF2 activation in (i) promoting rapid-onset, multifocal intrabronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in -mutant, -null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment.

CONCLUSIONS

Our modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with loss and activation to promote aggressive lung adenocarcinoma. In patients, oncogenic events alter the tumor immune contexture, possibly having an impact on treatment responses. Importantly, patients with NRF2-activated nonsquamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment.