Journal
CANCER CELL
Volume 23, Issue 2, Pages 143-158Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2012.12.008
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Funding
- National Center for Advancing Translational Sciences through UCLA CTSI grant [UL1TR000124, KL2TR000122]
- National Institutes of Health [R01 DK080425, P01CA120964]
- American Cancer Society Research Scholar Award [RSG-07-210-01-MGO]
- Salk CCSG [P30 CA014195]
- Samuel Waxman Cancer Research Foundation
- [S10RR026744]
- [T32 CA009370]
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The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in similar to 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.
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