1. LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin
- Author
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Evan R. Abt, Johannes Czernin, David B. Shackelford, Debbie S. Vasquez, Michael C. Fishbein, Laurie Gerken, Atsuko Seki, Reuben J. Shaw, Liu Wei, Paul S. Mischel, and Mathias Leblanc
- Subjects
Cancer Research ,Lung Neoplasms ,Cell ,Eukaryotic Initiation Factor-2 ,Apoptosis ,Phenformin ,Pharmacology ,AMP-Activated Protein Kinases ,medicine.disease_cause ,chemistry.chemical_compound ,Mice ,0302 clinical medicine ,Carcinoma, Non-Small-Cell Lung ,skin and connective tissue diseases ,Cells, Cultured ,Mice, Knockout ,0303 health sciences ,Kinase ,Reverse Transcriptase Polymerase Chain Reaction ,3. Good health ,Metformin ,Mitochondria ,medicine.anatomical_structure ,Oncology ,030220 oncology & carcinogenesis ,KRAS ,medicine.drug ,congenital, hereditary, and neonatal diseases and abnormalities ,Blotting, Western ,STK11 ,Biology ,Protein Serine-Threonine Kinases ,Real-Time Polymerase Chain Reaction ,Article ,Proto-Oncogene Proteins p21(ras) ,03 medical and health sciences ,medicine ,Animals ,Humans ,Hypoglycemic Agents ,RNA, Messenger ,Lung cancer ,neoplasms ,030304 developmental biology ,Cell Proliferation ,Cell growth ,Cell Biology ,medicine.disease ,respiratory tract diseases ,chemistry ,Mutation ,Tumor Suppressor Protein p53 - Abstract
SummaryThe 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.
- Published
- 2011