TY - JOUR
T1 - NRF2 Activation promotes aggressive lung cancer and associates with poor clinical outcomes
AU - Singh, Anju
AU - Daemen, Anneleen
AU - Nickles, Dorothee
AU - Jeon, Sang Min
AU - Foreman, Oded
AU - Sudini, Kuladeep
AU - Gnad, Florian
AU - Lajoie, Stephane
AU - Gour, Naina
AU - Mitzner, Wayne
AU - Chatterjee, Samit
AU - Choi, Eun Ji
AU - Ravishankar, Buvana
AU - Rappaport, Amy
AU - Patil, Namrata
AU - McCleland, Mark
AU - Johnson, Leisa
AU - Acquaah-Mensah, George
AU - Gabrielson, Edward
AU - Biswal, Shyam
AU - Hatzivassiliou, Georgia
N1 - Funding Information:
Part of this work was supported by grants from the National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea (1420320, HA17C0033) and the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (NRF-2017R1C1B2003162; to S.-M. Jeon). A. Singh was supported by Flight Attendant Medical Research Institute and Maryland Cigarette Restitution Fund. S. Biswal is supported with NIH R01CA206155. We would like to thank Melissa R. Junttila for critical comments on the manuscript and Scott Foster for helpful discussions.
Funding Information:
A. Singh reports grants from FAMRI during the conduct of the study; in addition, A. Singh has a patent 8216777 issued. A. Daemen reports personal fees from ORIC Pharmaceuticals outside the submitted work; in addition, A. Daemen has a patent for WO 2010/12717 issued and a patent for WO 2013/133876 issued. D. Nickles reports other from Roche outside the submitted work. S.-M. Jeon reports grants from National R&D Program for Cancer Control, Ministry of Health & Welfare, Republic of Korea and grants from Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning during the conduct of the study; in addition, S.-M. Jeon has a patent for Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound pending (China, US) and licensed to SCL Therapeutics and a patent for Pharmaceutical composition for treatment of lung cancer comprising glucocorticoid-based compound issued (Korea) and licensed to SCL Therapeutics. M. McCleland reports other from Genentech outside the submitted work. L. Johnson reports non-financial support from Johns Hopkins University during the conduct of the study; other from 4D Molecular Therapeutics (4DMT) outside the submitted work. S. Biswal reports a patent for 8216777 issued. No disclosures were reported by the other authors.
Publisher Copyright:
© 2020 American Association for Cancer Research.
PY - 2021/2/1
Y1 - 2021/2/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-20-1985
DO - 10.1158/1078-0432.CCR-20-1985
M3 - Article
C2 - 33077574
AN - SCOPUS:85100435980
VL - 27
SP - 877
EP - 888
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 3
ER -