아주대학교, Genentech Inc., 현 아주대학교, SCL Therapeutics

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NRF2 activation promotes aggressive lung cancer and associates with poor clinical outcomes
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Abstract

Purpose: Stabilization of the transcription factor NRF2 through genomic alterations in KEAP1 and NFE2L2 occurs in a quarter of lung adenocarcinoma (LUAD) and a third of lung squamous (LUSC) patients. In LUAD, KEAP1 loss often co-occurs with STK11 loss and KRAS activating alterations. Despite its prevalence, the impact of NRF 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. Further, 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, multi-focal intra-bronchiolar carcinomas, leading to lethal pulmonary dysfunction, and (ii) decreasing elevated redox stress in KRAS-mutant, STK11-null tumors. In patients with non-squamous tumors, the NRF2 signature is negatively prognostic independently of STK11 loss. LUSC patients 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 LUAD. In patients, oncogenic events alter the tumor immune contexture, possibly impacting treatment responses. Importantly, patients with NRF2 activated non-squamous or squamous tumors have poor prognosis and show limited response to anti-PD-L1 treatment.

Keywords: Non-small cell lung cancer; NRF2; immunotherapy; predictive biomarker; genetically engineered mouse model

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- 형식: Research article
- 게재일: 2020년 10월 (BRIC 등록일 2020-10-20)
- 연구진: 국내+국외 연구진
- 분야: Cancer Biology/Oncology
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