NRF2 Activation promotes aggressive lung cancer and associates with poor clinical outcomes

Anju Singh, Anneleen Daemen, Dorothee Nickles, Sang Min Jeon, Oded Foreman, Kuladeep Sudini, Florian Gnad, Stephane Lajoie, Naina Gour, Wayne Mitzner, Samit Chatterjee, Eun Ji Choi, Buvana Ravishankar, Amy Rappaport, Namrata Patil, Mark McCleland, Leisa Johnson, George Acquaah-Mensah, Edward Gabrielson, Shyam BiswalGeorgia Hatzivassiliou

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of patients with lung adenocarcinoma and a third of patients with lung squamous cell carcinoma. In lung adenocarcinoma, KEAP1 loss often co-occurs with STK11 loss and KRAS-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, STK11 loss, and KRAS activation in vivo 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 in vivo 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 KRAS-mutant, STK11-null tumors. In patients with nonsquamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. Patients with lung squamous cell carcinoma with low NRF2 signature survive longer when receiving anti-PD-L1 treatment. Conclusions: Our in vivo modeling establishes NRF2 activation as a critical oncogenic driver, cooperating with STK11 loss and KRAS 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.

Original languageEnglish (US)
Pages (from-to)877-888
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number3
DOIs
StatePublished - Feb 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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