Department of Environmental Health Science and Engineering, Johns Hopkins University School of Public Health, Baltimore, Maryland.
Oncology Bioinformatics, Genentech Inc., South San Francisco, California.
Clin Cancer Res. 2021 Feb 1;27(3):877-888. doi: 10.1158/1078-0432.CCR-20-1985. Epub 2020 Oct 19.
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.
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.
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.
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.
在四分之一的肺腺癌患者和三分之一的肺鳞癌患者中，通过 和 中的基因组改变稳定转录因子 NRF2。在肺腺癌中， 缺失常与 缺失和 -激活改变同时发生。尽管 NRF2 激活很常见，但它对肿瘤进展和患者预后的影响尚未完全明确。
我们使用新型基因工程小鼠模型来模拟 NRF2 激活、 缺失和 激活。此外，我们从非小细胞肺癌肿瘤中提取了 NRF2 激活特征，用于剖析这些基因组事件如何影响 OAK 和 IMpower131 免疫治疗试验参与者的结局和免疫结构。
我们的 数据揭示了 NRF2 激活在以下方面的作用：（i）促进快速发生的多灶性支气管内癌，导致致命性肺功能障碍；（ii）降低 -突变、-缺失肿瘤中升高的氧化还原应激。在非鳞状肿瘤患者中，NRF2 特征独立于 缺失具有负预后意义。接受抗 PD-L1 治疗的肺鳞癌患者中，NRF2 特征低者存活时间更长。
我们的 模型建立了 NRF2 激活作为关键致癌驱动因素的作用，与 缺失和 激活协同促进侵袭性肺腺癌。在患者中，致癌事件改变了肿瘤免疫结构，可能对治疗反应产生影响。重要的是，NRF2 激活的非鳞状或鳞状肿瘤患者预后不良，对抗 PD-L1 治疗反应有限。
