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LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS -Mutant Lung Adenocarcinoma
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Abstract
In KRAS-mutant lung adenocarcinoma, tumors with LKB1 loss (KL) are highly enriched for concurrent KEAP1 mutations, which activate the KEAP1/NRF2 pathway (KLK). Here, we investigated the biological consequences of these cooccurring alterations and explored whether they conferred specific therapeutic vulnerabilities. Compared with KL tumors, KLK tumors exhibited increased expression of genes involved in glutamine metabolism, the tricarboxylic acid cycle, and the redox homeostasis signature. Using isogenic pairs with knockdown or overexpression of LKB1, KEAP1, and NRF2, we found that LKB1 loss results in increased energetic and redox stress marked by increased levels of intracellular reactive oxygen species and decreased levels of ATP, NADPH/NADP+ ratio, and glutathione. Activation of the KEAP1/NRF2 axis in LKB1-deficient cells enhanced cell survival and played a critical role in the maintenance of energetic and redox homeostasis in a glutamine-dependent manner. LKB1 and the KEAP1/NRF2 pathways cooperatively drove metabolic reprogramming and enhanced sensitivity to the glutaminase inhibitor CB-839 in vitro and in vivo. Overall, these findings elucidate the adaptive advantage provided by KEAP1/NRF2 pathway activation in KL tumors and support clinical testing of glutaminase inhibitor in subsets of KRAS-mutant lung adenocarcinoma. Significance: In KRAS-mutant non–small cell lung cancer, LKB1 loss results in enhanced energetic/redox stress, which is tolerated, in part, through cooccurring KEAP1/NRF2–dependent metabolic adaptations, thus enhancing glutamine dependence and vulnerability to glutaminase inhibition.
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In the citing paper
“we did not identify targets related to pathways previously investigated for STK11-mutant cancer therapy, such as glutamine synthesis (37) or mTOR signaling (38, 39).”
From TNG260 Is a Small-Molecule CoREST Inhibitor That Sensitizes STK11 -Mutant Tumors to Anti–PD-1 Immunotherapy (2025) · cites this paper as [37]
Experimental — accuracy not yet measuredIn the citing paper
“Separately, the loss of LKB1 in mutant KRAS non-small cell lung cancer preclinical mouse model was found to promote NRF2-dependent metabolic alterations that increased the tumor cells’ dependence on glutamine and created a vulnerability to glutaminase inhibition66.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [66]
In the citing paper
“Thus, cancer cells harboring KRAS, KEAP1 and LKB1 mutations may be more sensitive to glutaminase inhibition compared to normal counterparts66.”
From The metabolic landscape of RAS-driven cancers from biology to therapy (2021) · cites this paper as [66]
In the citing paper
“Thus, NRF2- mediated metabolic reprogramming and regulation of redox homeostasis likely underpin the strong co-selection of KEAP1 with LKB1 and KRAS mutations in NSCLC at least partially because oncogenic KRAS itself promotes oxidative stress and anabolic metabolism and because KL NSCLC cells depend on the pentose phosphate pathway for NAPDH generation and for detoxification of reactive oxygen”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [97]
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Metadata
- Authors
- Galan-Cobo, A., Sitthideatphaiboon, P., Qu, X., Poteete, A., Pisegna, M. A., Tong, P., Chen, P.-H., Boroughs, L. K., Rodriguez, M. L. M., Zhang, W., Parlati, F., Wang, J., Gandhi, V., Skoulidis, F., DeBerardinis, R. J., Minna, J. D., & Heymach, J. V.
- Affiliations
- 1Department of Thoracic, Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- Chulalongkorn University (TH)
- Shandong University (CN)
- The University of Texas MD Anderson Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- 619946 Hibiscus Dr., Jupiter, Florida.
- Calithera (United States) (US)
- Children's Medical Center (US)
- Harold C. Simmons Comprehensive Cancer Center (US)
- Corresponding author
- Heymach, John V.
- ORCID
- Venue
- Cancer Research
- Published
- 2019-07-01
- Volume
- 79
- Issue
- 13
- Pages
- 3251-3267
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC6606351
- OpenAlex
- W2943618951
- Cited by
- 292
- References
- 55
- Citations by year
- 2026: 33 · 2025: 36 · 2024: 37 · 2023: 41 · 2022: 55 · 2021: 45 · 2020: 35 · 2019: 10
- FWCI
- 12.00
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- HHS | NIH | National Cancer InstituteHHS | NIH | National Cancer Institute (NCI) (P50CA07907, CA016672)
- HHS | NIH | National Center for Research ResourcesHHS | NIH | National Center for Research Resources (NCRR) (CA205150)
- Cancer Prevention and Research Institute of TexasCancer Prevention and Research Institute of Texas (CPRIT) (CP160652)
- American Association for Cancer ResearchAmerican Association for Cancer Research (AACR) (SU2C-AACR-DT17-15)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics, phytochemicals, and oxidative stress
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- LKB1, Nrf2/Keap1 pathway, KRAS-mutant lung adenocarcinoma, metabolic reprogramming, glutamine addiction, glutaminase inhibition, CB-839, redox homeostasis, energy stress, reactive oxygen species, NADPH/NADP+ ratio, glutathione, TCA cycle
- MeSH terms
- Kelch-Like ECH-Associated Protein 1, Adenocarcinoma of Lung, AMP-Activated Protein Kinase Kinases, Adenosine Triphosphate, Animals, Carcinoma, Non-Small-Cell Lung, Energy Metabolism, Female, Glutaminase, Glutamine, Humans, Lung Neoplasms, Mice, Inbred BALB C, Mice, Nude, Mutation, Tumor Cells, Cultured, Biomarkers, Tumor, Signal Transduction, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Mice, SCID, Mice, Inbred NOD, Apoptosis, Protein Serine-Threonine Kinases, Oxidative Stress, Xenograft Model Antitumor Assays, Cell Proliferation, NF-E2-Related Factor 2, Mice, Metabolic Networks and Pathways, Cellular Reprogramming
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