Evidence map›Paper›PMID 39048991›Full record

ArticleMolecular cancer2024

Loss of the tumour suppressor LKB1/STK11 uncovers a leptin-mediated sensitivity mechanism to mitochondrial uncouplers for targeted cancer therapy.

Andriani Angelopoulou, Giorgos Theocharous, Dimitrios Valakos, Aikaterini Polyzou, Sophia Magkouta, Vassilios Myrianthopoulos, Sophia Havaki, Marco Fiorillo, Ioanna Tremi, Konstantinos Vachlas and 10 more

Erratum issuedAbstract readLetter
PubMed Full text at PMC Publisher
In one paragraph

Article in Molecular cancer, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 16 papers.

0numbers the graph read from it
0cells of the map it votes in
16citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

16 citing papers in PubMed.

  1. Article
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  4. Current oncology (Toronto, Ont.) · 2026
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  7. Article
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  11. Interrogating the regulatory epigenome of cellular senescence.Cellular and molecular life sciences : CMLS · 2025
    Review
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4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

20 authors.

Andriani AngelopoulouMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Giorgos TheocharousMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Dimitrios ValakosBiomedical Research Foundation, Academy of Athens, Athens, Greece.
Aikaterini PolyzouMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Sophia MagkoutaMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Vassilios MyrianthopoulosDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Athens, Athens, 15772, Greece.
Sophia HavakiMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Marco FiorilloDepartment of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende, 87036, Italy.
Ioanna TremiMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Konstantinos VachlasThoracic Surgery Department, "Sotiria" Hospital, Athens, 115 27, Greece.
Theodoros NisotakisMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Dimitris-Foivos ThanosMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
Anastasia PantazakiLaboratory of Biochemistry, Department of Chemistry, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece.
Dimitris KletsasLaboratory of Cell Proliferation and Ageing, Institute of Biosciences and Applications, National Centre for Scientific Research "Demokritos", Athens, 15341, Greece.
Jiri BartekGenome Integrity Group, Danish Cancer Society Research Center, Copenhagen, 2100, Denmark.
Russell PettyNinewells Hospital and Medical School, University of Dundee, Dundee, UK.
Dimitris ThanosBiomedical Research Foundation, Academy of Athens, Athens, Greece.
Rory J McCrimmonNinewells Hospital and Medical School, University of Dundee, Dundee, UK.
Angelos PapaspyropoulosMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. a.papaspyropoulos@med.uoa.gr.
Vassilis G GorgoulisMolecular Carcinogenesis Group, Department of Histology and Embryology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. vgorg@med.uoa.gr.

Funding

European Regional Development Fund of the European Union T2EDK-02939 and T2EDK-03266European Social Fund 2019-050-0503-18066Foundation for Education and European Culture IPEPGeneral Secretariat for Research and Technology 2020ΣΕ01300001Hellenic Foundation for Research and Innovation 3782Hellenic Foundation for Research and Innovation 5747KWF Kankerbestrijding KWF UL 2012-5395SARG, National Kapodistrian University of Athens 70/3/8916Sonia Kotopoulos Donation
6 · The paper itself

Abstract

Non-small cell lung cancer (NSCLC) constitutes one of the deadliest and most common malignancies. The LKB1/STK11 tumour suppressor is mutated in ∼ 30% of NSCLCs, typically lung adenocarcinomas (LUAD). We implemented zebrafish and human lung organoids as synergistic platforms to pre-clinically screen for metabolic compounds selectively targeting LKB1-deficient tumours. Interestingly, two kinase inhibitors, Piceatannol and Tyrphostin 23, appeared to exert synthetic lethality with LKB1 mutations. Although LKB1 loss alone accelerates energy expenditure, unexpectedly we find that it additionally alters regulation of the key energy homeostasis maintenance player leptin (LEP), further increasing the energetic burden and exposing a vulnerable point; acquired sensitivity to the identified compounds. We show that compound treatment stabilises Hypoxia-inducible factor 1-alpha (HIF1A) by antagonising Von Hippel-Lindau (VHL)-mediated HIF1A ubiquitination, driving LEP hyperactivation. Importantly, we demonstrate that sensitivity to piceatannol/tyrphostin 23 epistatically relies on a HIF1A-LEP-Uncoupling Protein 2 (UCP2) signaling axis lowering cellular energy beyond survival, in already challenged LKB1-deficient cells. Thus, we uncover a pivotal metabolic vulnerability of LKB1-deficient tumours, which may be therapeutically exploited using our identified compounds as mitochondrial uncouplers.

Indexed as

AMP-Activated Protein Kinase KinasesLeptinMitochondriaProtein Serine-Threonine KinasesZebrafishAnimalsCarcinoma, Non-Small-Cell LungCell Line, TumorHumansHypoxia-Inducible Factor 1, alpha SubunitLung NeoplasmsMolecular Targeted TherapyProtein Kinase InhibitorsStilbenesUncoupling Agents3,3',4,5'-tetrahydroxystilbeneAMP-Activated Protein Kinase KinasesHypoxia-Inducible Factor 1, alpha SubunitLeptinProtein Kinase InhibitorsProtein Serine-Threonine KinasesStilbenesSTK11 protein, humanUncoupling AgentsAirway organoidsCRISPR/Cas9-mediated genome editingDrug discoveryHIF1A-LEP-UCP2 axisLKB1/STK11Metabolic stressNon-small cell lung cancer (NSCLC)PiceatannolTyrphostin 23Zebrafish

Identifiers

PMID39048991
PMCPMC11270803

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.