LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.
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.
Molecular and Cell Biology Laboratory, Dulbecco Center for Cancer Research, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA. dshackelford@mednet.ucla.edu
David B
DB
Shackelford
Evan
E
Abt
Laurie
L
Gerken
Debbie S
DS
Vasquez
Atsuko
A
Seki
Mathias
M
Leblanc
Liu
L
Wei
Michael C
MC
Fishbein
Johannes
J
Czernin
Paul S
PS
Mischel
Reuben J
RJ
Shaw
D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics; D010629:Phenformin / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D015852:Eukaryotic Initiation Factor-2; D007004:Hypoglycemic Agents; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53; D010629:Phenformin; D017346:Protein Serine-Threonine Kinases; C491654:Stk11 protein, mouse; D055372:AMP-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)