LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin.
Published
Journal Article
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.
Full Text
Duke Authors
Cited Authors
- Shackelford, DB; Abt, E; Gerken, L; Vasquez, DS; Seki, A; Leblanc, M; Wei, L; Fishbein, MC; Czernin, J; Mischel, PS; Shaw, RJ
Published Date
- February 2013
Published In
Volume / Issue
- 23 / 2
Start / End Page
- 143 - 158
PubMed ID
- 23352126
Pubmed Central ID
- 23352126
Electronic International Standard Serial Number (EISSN)
- 1878-3686
International Standard Serial Number (ISSN)
- 1535-6108
Digital Object Identifier (DOI)
- 10.1016/j.ccr.2012.12.008
Language
- eng