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Cancer Cell. 2013 Feb 11;23(2):143-58. doi: 10.1016/j.ccr.2012.12.008. Epub 2013 Jan 24.

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

Author information

1
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

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.

PMID:
23352126
PMCID:
PMC3579627
DOI:
10.1016/j.ccr.2012.12.008
[Indexed for MEDLINE]
Free PMC Article

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