ArticleNature metabolism2024
Concurrent loss of LKB1 and KEAP1 enhances SHMT-mediated antioxidant defence in KRAS-mutant lung cancer.
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Article in Nature metabolism, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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22citing papers in PubMed
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Who cites it
22 citing papers in PubMed.
- Genes, fuel, and fate in lung cancer.Biochemical Society transactions · 2026Review
- Molecular insights and therapeutic implications for the tumor suppressor role of LKB1 in non-small cell lung cancer.Cancer letters · 2026Review
- Amino Acids as Targets for Immunotherapy against Solid Tumors.Cell biochemistry and biophysics · 2026Review
- Serine Hydroxymethyltransferase (SHMT) in biology and disease: molecular mechanisms and therapeutic targeting.Journal of translational medicine · 2026Review
- Metabolic reprogramming in cancer: signaling pathways and therapeutic targets.Molecular cancer · 2026Review
- SLC46A1 deficiency-mediated folate restriction suppresses colorectal cancer progression through epigenetic-transcriptional reprogramming.Cell death & disease · 2026Article
- Targeting serine synthesis pathway to reverse paclitaxel resistance in NSCLC with combination of paclitaxel and anlotinib.Journal of experimental & clinical cancer research : CR · 2026Article
- Wise as a Serpent and Gentle as a Dove: Pharmacological Targeting of NRF2/KEAP1 Pathway from Treasure Trove of Mother Nature.Drug design, development and therapy · 2026Review
- Amino acids metabolism: a potential target for cancer treatment.Molecular cancer · 2025Review
- ZNF526 drives tumor growth by enhancing SHMT1-dependent serine metabolism and antioxidant capability in TNBC.Molecular cancer · 2025Article
- Integrative analysis of lung adenocarcinoma across diverse ethnicities and exposures.Cancer cell · 2025Article
- Multifaceted role of serine hydroxymethyltransferase in health and disease.Molecules and cells · 2025Review
- Mitochondrial metabolism and cancer therapeutic innovation.Signal transduction and targeted therapy · 2025Review
- Targeting LKB1/STK11-mutant cancer: distinct metabolism, microenvironment, and therapeutic resistance.Trends in pharmacological sciences · 2025Review
- The oncoprotein SET promotes serine-derived one-carbon metabolism by regulating SHMT2 enzymatic activity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Amino acids in cancer: Understanding metabolic plasticity and divergence for better therapeutic approaches.Cell reports · 2025Review
- Integrative bioinformatics approach identifies novel drug targets for hyperaldosteronism, with a focus on SHMT1 as a promising therapeutic candidate.Scientific reports · 2025Article
- Metabolic reprogramming and therapeutic targeting in non-small cell lung cancer: emerging insights beyond the Warburg effect.Frontiers in oncology · 2025Review
- Kelch-like ECH-associated Protein 1/Nuclear Factor Erythroid 2-related Factor 2 Pathway and Its Interplay with Oncogenes in Lung Tumorigenesis.Journal of cancer prevention · 2024Review
- Understanding serine and glycine metabolism in cancer: a path towards precision medicine to improve patient's outcomes.Discover oncology · 2024Review
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Authors and funding
23 authors.
Hyun Min LeeDepartment of Urology, Yale School of Medicine, New Haven, CT, USA.ORCID http://orcid.org/0009-0007-4923-6275
Nefertiti MuhammadDepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Elizabeth L LieuDepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Feng CaiChildren's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.
Jiawei MuDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
Yun-Sok HaDepartment of Urology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, Korea.
Guoshen CaoDepartment of Biochemistry, University of Utah, Salt Lake City, UT, USA.ORCID http://orcid.org/0009-0007-7378-6306
Chamey SuchorsHamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.
Kenneth JovesDepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Constantinos ChronisDepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Kailong LiDepartment of Biochemistry and Biophysics, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.ORCID http://orcid.org/0000-0001-5369-354X
Gregory S DuckerDepartment of Biochemistry, University of Utah, Salt Lake City, UT, USA.ORCID http://orcid.org/0000-0002-8651-6846
Kellen OlszewskiBarer Institute, Philadelphia, PA, USA.
Ling CaiDepartment of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.
Derek B AllisonDepartment of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
Sara E BachertDepartment of Pathology and Laboratory Medicine, University of Kentucky College of Medicine, Lexington, KY, USA.
William R EwingBarer Institute, Philadelphia, PA, USA.
Harvey WongFaculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, BC, Canada.ORCID http://orcid.org/0000-0003-1550-5071
Hyosun SeoDepartment of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.
Isaac Y KimDepartment of Urology, Yale School of Medicine, New Haven, CT, USA.
Brandon FaubertDepartment of Medicine-Hematology and Oncology, University of Chicago, Chicago, IL, USA.ORCID http://orcid.org/0000-0002-2886-886X
James KimHamon Center for Therapeutic Oncology Research, UT Southwestern Medical Center, Dallas, TX, USA.
Jiyeon KimDepartment of Urology, Yale School of Medicine, New Haven, CT, USA. jiyeon.kim1@yale.edu.ORCID http://orcid.org/0000-0002-0138-1920
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MUNIVERSITY OF TEXAS--SPORE IN LUNG CANCERP50CA070907 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI HEYMACH, JOHN V., MINNA, JOHN D. · 1996 to 2024
$57.4MUniversity of Kentucky Markey Cancer Center Support Grant ECIA SupplementP30CA177558 · NCI · UNIVERSITY OF KENTUCKY · PI Bernard Mark Evers · 2013 to 2026
$38.3MYale SPORE in Lung Cancer (YSILC): The Biology and Personalized Treatment of Lung CancerP50CA196530 · NCI · YALE UNIVERSITY · PI Kurt A Schalper · 2015 to 2026
$31.1MThe Lung Endothelium as an Instructive Niche for the Innate Immune System during Vascular InjuryP01HL160469 · NHLBI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI DOLLY MEHTA · 2022 to 2026
$14.0MRegulation of GLI1, a synthetic lethal target of SMARCA4-deficiency, in lung adenocarcinomaR01CA258684 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI KIM, JAMES · 2021 to 2025
$1.9MUncovering Oncogenotype-specific Vulnerabilities in Lung cancerR37CA285640 · NCI · YALE UNIVERSITY · PI Jiyeon Kim · 2024 to 2026
$1.8MTargeting vismodegib-resistant tumors using BH3 mimeticsR01CA196851 · NCI · UT SOUTHWESTERN MEDICAL CENTER · PI KIM, JAMES · 2016 to 2020
$1.7MGlycine metabolism in cancer - Research Supplement to Promote Diversity in Health-Related Research; VelascoR00CA215307 · NCI · UNIVERSITY OF UTAH · PI DUCKER, GREGORY S · 2019 to 2021
$814kIdentifying factors regulating cancer metabolism in vivoR00CA237724 · NCI · UNIVERSITY OF CHICAGO · PI FAUBERT, BRANDON · 2022 to 2024
$667kTargeting altered nitrogen metabolism in an aggressive subset of human lung canceK22CA226676 · NCI · UNIVERSITY OF ILLINOIS AT CHICAGO · PI KIM, JIYEON · 2019 to 2021
$591kAmerican Cancer Society (American Cancer Society, Inc.) RSG-21-153-01-CCBAmerican Lung Association (Lung Association) IA-828202NCATS NIH HHS UL1 TR001863NCI NIH HHS K22 CA226676NCI NIH HHS P30 CA177558NCI NIH HHS P50 CA070907NCI NIH HHS P50 CA196530NCI NIH HHS R00 CA215307NCI NIH HHS R00 CA237724NCI NIH HHS R01 CA196851NCI NIH HHS R01 CA258684NCI NIH HHS R37 CA285640NHLBI NIH HHS P01 HL160469U.S. Department of Health & Human Services | National Institutes of Health (NIH) 1R01CA196851U.S. Department of Health & Human Services | National Institutes of Health (NIH) P01HL160469U.S. Department of Health & Human Services | National Institutes of Health (NIH) P50CA070907U.S. Department of Health & Human Services | National Institutes of Health (NIH) R00CA215307U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) 1K22CA226676-01A1U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) P30CA177558U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI) R00CA237724U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics) 1R01CA258684U.S. Department of Health & Human Services | NIH | NCI | Division of Cancer Epidemiology and Genetics, National Cancer Institute (National Cancer Institute Division of Cancer Epidemiology and Genetics) 1R37CA285640-01A1
Abstract
Non-small-cell lung cancer (NSCLC) with concurrent mutations in KRAS and the tumour suppressor LKB1 (KL NSCLC) is refractory to most therapies and has one of the worst predicted outcomes. Here we describe a KL-induced metabolic vulnerability associated with serine-glycine-one-carbon (SGOC) metabolism. Using RNA-seq and metabolomics data from human NSCLC, we uncovered that LKB1 loss enhanced SGOC metabolism via serine hydroxymethyltransferase (SHMT). LKB1 loss, in collaboration with KEAP1 loss, activated SHMT through inactivation of the salt-induced kinase (SIK)-NRF2 axis and satisfied the increased demand for one-carbon units necessary for antioxidant defence. Chemical and genetic SHMT suppression increased cellular sensitivity to oxidative stress and cell death. Further, the SHMT inhibitor enhanced the in vivo therapeutic efficacy of paclitaxel (first-line NSCLC therapy inducing oxidative stress) in KEAP1-mutant KL tumours. The data reveal how this highly aggressive molecular subtype of NSCLC fulfills their metabolic requirements and provides insight into therapeutic strategies.
Indexed as
AMP-Activated Protein Kinase KinasesAntioxidantsCarcinoma, Non-Small-Cell LungGlycine HydroxymethyltransferaseKelch-Like ECH-Associated Protein 1Lung NeoplasmsMutationProtein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)AnimalsCell Line, TumorHumansMiceNF-E2-Related Factor 2Oxidative StressAMP-Activated Protein Kinase KinasesAntioxidantsGlycine HydroxymethyltransferaseKEAP1 protein, humanKelch-Like ECH-Associated Protein 1KRAS protein, humanNFE2L2 protein, humanNF-E2-Related Factor 2Protein Serine-Threonine KinasesProto-Oncogene Proteins p21(ras)SHMT protein, humanSTK11 protein, human
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