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

Abstract

Stabilization of the transcription factor NRF2 through genomic alterations in <i>KEAP1</i> and <i>NFE2L2</i> occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, <i>KEAP1</i> loss often co-occurs with <i>STK11</i> loss and <i>KRAS</i>-activating alterations. Despite its prevalence, the impact of NRF2 activation on tumor progression and patient outcomes is not fully defined. We model NRF2 activation, <i>STK11</i> loss, and <i>KRAS</i> activation <i>in vivo</i> 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. Our <i>in vivo</i> 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 <i>KRAS</i>-mutant, <i>STK11</i>-null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of <i>STK11</i> loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment. Our <i>in vivo</i> modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with <i>STK11</i> loss and <i>KRAS</i> 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.