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LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin
Open accessAbstract
The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.
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“or the combination of phenformin with the mTOR inhibitor MLN0128157”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [157]
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Metadata
- Authors
- Shackelford, D. B., Abt, E., Gerken, L., Vasquez, D. S., Seki, A., Leblanc, M., Wei, L., Fishbein, M. C., Czernin, J., Mischel, P. S., & Shaw, R. J.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California, Los Angeles (US)
- Corresponding author
- Shackelford, David B.
- Shaw, Reuben J.
- ORCID
- Venue
- Cancer Cell
- Publisher
- Elsevier BV
- Published
- 2013-02
- Volume
- 23
- Issue
- 2
- Pages
- 143-158
- ISSN
- 1535-6108 (ISSN-L)
- PMC
- PMC3579627
- OpenAlex
- W2135617839
- Cited by
- 585
- References
- 53
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 32 · 2023: 34 · 2022: 33 · 2021: 53 · 2020: 46 · 2019: 45 · 2018: 46 · 2017: 58 · 2016: 44 · 2015: 62 · 2014: 54 · 2013: 36
- FWCI
- 29.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cancer Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (UL1TR000124, KL2TR000122)
- National Cancer Institute (R01CA172229, P01CA120964, T32CA009370, P30CA014195)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK080425)
- National Center for Research Resources (S10RR026744)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- 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, STK11, non-small cell lung cancer, phenformin, cancer metabolism, AMPK, mitochondrial inhibition, apoptosis, KRAS mutation, TP53 mutation, tumor suppressor inactivation, metabolic therapy
- MeSH terms
- Animals, Carcinoma, Non-Small-Cell Lung, Cells, Cultured, Humans, Hypoglycemic Agents, Lung Neoplasms, Mitochondria, Mutation, Phenformin, RNA, Messenger, Blotting, Western, Eukaryotic Initiation Factor-2, Tumor Suppressor Protein p53, Proto-Oncogene Proteins p21(ras), Apoptosis, Protein Serine-Threonine Kinases, Mice, Knockout, Reverse Transcriptase Polymerase Chain Reaction, Cell Proliferation, Mice, AMP-Activated Protein Kinases, Real-Time Polymerase Chain Reaction
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