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LKB1 Loss Induces Characteristic Patterns of Gene Expression in Human Tumors Associated with NRF2 Activation and Attenuation of PI3K-AKT
Open accessAbstract
INTRODUCTION: Inactivation of serine/threonine kinase 11 (STK11 or LKB1) is common in lung cancer, and understanding the pathways and phenotypes altered as a consequence will aid the development of targeted therapeutic strategies. Gene and protein expressions in a murine model of v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (Kras)-mutant lung cancer have been studied to gain insight into the biology of these tumors. However, the molecular consequences of LKB1 loss in human lung cancer have not been fully characterized. METHODS: We studied gene expression profiles associated with LKB1 loss in resected lung adenocarcinomas, non-small-cell lung cancer cell lines, and murine tumors. The biological significance of dysregulated genes was interpreted using gene set enrichment and transcription factor analyses and also by integration with somatic mutations and proteomic data. RESULTS: Loss of LKB1 is associated with consistent gene expression changes in resected human lung cancers and cell lines that differ substantially from the mouse model. Our analysis implicates novel biological features associated with LKB1 loss, including altered mitochondrial metabolism, activation of the nuclear respiratory factor 2 (NRF2) transcription factor by kelch-like ECH-associated protein 1 (KEAP1) mutations, and attenuation of the phosphatidylinositiol 3-kinase and v-akt murine thymoma viral oncogene homolog (PI3K/AKT) pathway. Furthermore, we derived a 16-gene classifier that accurately predicts LKB1 mutations and loss by nonmutational mechanisms. In vitro, transduction of LKB1 into LKB1-mutant cell lines results in attenuation of this signature. CONCLUSION: Loss of LKB1 defines a subset of lung adenocarcinomas associated with characteristic molecular phenotypes and distinctive gene expression features. Studying these effects may improve our understanding of the biology of these tumors and lead to the identification of targeted treatment strategies.
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“Moreover, in oncogenic-KRAS-driven lung adenocarcinoma, loss of LKB1 often induces KEAP1 activation69 and leads to metabolic alterations that could be counteracted by activation of NRF270, thereby maintaining redox homeostasis and fueling energy metabolism in a glutamine-dependent manner.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [69]
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“This indicates a potential selective pressure existing for the activation of the antioxidant KEAP1/ NRF2 pathway to compensate for oxidative stress induced by LKB1 loss [66].”
BackgroundLKB1 drives stasis and C/EBP-mediated reprogramming to an alveolar type II fate in lung cancer
Murray, C. W., Brady, J. J., Han, M., Cai, H., Tsai, M. K., Pierce, S. E., Cheng, R., Demeter, J., Feldser, D. M., Jackson, P. K., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-28619-8 · Cited by 22
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Metadata
- Authors
- Kaufman, J. M., Amann, J. M., Park, K., Arasada, R. R., Li, H., Shyr, Y., & Carbone, D. P.
- Affiliations
- University of Kentucky (US)
- The Ohio State University (US)
- Vanderbilt University (US)
- Corresponding author
- Carbone, David P.
- Venue
- Journal of Thoracic Oncology
- Publisher
- Elsevier BV
- Published
- 2014-06
- Volume
- 9
- Issue
- 6
- Pages
- 794-804
- ISSN
- 1556-0864 (ISSN-L)
- PMC
- PMC4026179
- OpenAlex
- W2083855694
- Cited by
- 87
- References
- 48
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 9 · 2023: 7 · 2022: 5 · 2021: 12 · 2020: 9 · 2019: 9 · 2018: 1 · 2017: 6 · 2016: 10 · 2015: 6 · 2014: 2
- FWCI
- 6.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Thoracic Oncology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (U01CA114771, NCI U01CA114771, P30CA016058)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Keywords
- LKB1, STK11, lung adenocarcinoma, non-small cell lung cancer, gene expression profiling, Nrf2, KEAP1 mutation, PI3K/Akt signaling, mitochondrial metabolism, KRAS-mutant lung cancer, LKB1 loss
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, AMP-Activated Protein Kinase Kinases, Adenocarcinoma, Animals, Carcinoma, Non-Small-Cell Lung, Cytoskeletal Proteins, Multigene Family, Humans, Lung Neoplasms, Mitochondria, Mutation, Phosphorylation, Proto-Oncogene Proteins, RNA, Messenger, Signal Transduction, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Protein Serine-Threonine Kinases, ras Proteins, Cell Line, Tumor, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Proto-Oncogene Proteins c-akt, NF-E2-Related Factor 2, GA-Binding Protein Transcription Factor, Mice, AMP-Activated Protein Kinases, Phosphatidylinositol 3-Kinase, Transcriptome, Ataxia Telangiectasia Mutated Proteins, ErbB Receptors
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