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LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.

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.
AuthorsDavid 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
JournalCancer cell (Cancer Cell) Vol. 23 Issue 2 Pg. 143-58 (Feb 11 2013) ISSN: 1878-3686 [Electronic] United States
PMID23352126 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 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)
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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