Abstract |
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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Authors | David B Shackelford, Evan Abt, Laurie Gerken, Debbie S Vasquez, Atsuko Seki, Mathias Leblanc, Liu Wei, Michael C Fishbein, Johannes Czernin, Paul S Mischel, Reuben J Shaw |
Journal | Cancer cell
(Cancer Cell)
Vol. 23
Issue 2
Pg. 143-58
(Feb 11 2013)
ISSN: 1878-3686 [Electronic] United States |
PMID | 23352126
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Copyright | Copyright © 2013 Elsevier Inc. All rights reserved. |
Chemical References |
- Eukaryotic Initiation Factor-2
- Hypoglycemic Agents
- RNA, Messenger
- Tumor Suppressor Protein p53
- Phenformin
- Protein Serine-Threonine Kinases
- Stk11 protein, mouse
- AMP-Activated Protein Kinases
- Hras protein, mouse
- Proto-Oncogene Proteins p21(ras)
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Topics |
- AMP-Activated Protein Kinases
(genetics, metabolism)
- Animals
- Apoptosis
(drug effects)
- Blotting, Western
- Carcinoma, Non-Small-Cell Lung
(drug therapy, metabolism, pathology)
- Cell Proliferation
(drug effects)
- Cells, Cultured
- Eukaryotic Initiation Factor-2
(genetics, metabolism)
- Humans
- Hypoglycemic Agents
(therapeutic use)
- Lung Neoplasms
(drug therapy, metabolism, pathology)
- Mice
- Mice, Knockout
- Mitochondria
(drug effects, metabolism, pathology)
- Mutation
(genetics)
- Phenformin
(therapeutic use)
- Protein Serine-Threonine Kinases
(antagonists & inhibitors, physiology)
- Proto-Oncogene Proteins p21(ras)
(physiology)
- RNA, Messenger
(genetics)
- Real-Time Polymerase Chain Reaction
- Reverse Transcriptase Polymerase Chain Reaction
- Tumor Suppressor Protein p53
(physiology)
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