LKB1 inactivation dictates therapeutic response of non-small cell lung cancer to the metabolism drug phenformin
David 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, David 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
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.
Copyright © 2013 Elsevier Inc. All rights reserved.
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Source: PubMed