Cited by 292Genomics, phytochemicals, and oxidative stressCancer, Hypoxia, and MetabolismLung Cancer Treatments and Mutations

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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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Galan-Cobo, Ana, Sitthideatphaiboon, Piyada, Qu, Xiao, Poteete, Alissa, Pisegna, Marlese A., Tong, Pan, Chen, Pei-Hsuan, Boroughs, Lindsey K., Rodriguez, Mirna L.M., Zhang, Winter, Parlati, Francesco, Wang, Jing, Gandhi, Varsha, Skoulidis, Ferdinandos, DeBerardinis, Ralph J., Minna, John D., Heymach, John V.·2019·Cancer Research

DOI 10.1158/0008-5472.can-18-3527PMC PMC6606351

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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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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: Sitthideatphaiboon, Piyada
Qu, Xiao
Poteete, Alissa
Tong, Pan
Parlati, Francesco
Wang, Jing
Gandhi, Varsha
Skoulidis, Ferdinandos
DeBerardinis, Ralph J.
Minna, John D.
Heymach, John V.
Venue: Cancer Research
Publisher: American Association for Cancer Research (AACR)
Published: 2019-07-01
Volume: 79
Issue: 13
Pages: 3251-3267
ISSN: 0008-5472 (ISSN-L)
1538-7445
DOI: 10.1158/0008-5472.can-18-3527
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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LKB1 and KEAP1/NRF2 Pathways Cooperatively Promote Metabolic Reprogramming with Enhanced Glutamine Dependence in KRAS -Mutant Lung Adenocarcinoma

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