LKB1 Inactivation Dictates Therapeutic Response of Non-Small Cell Lung Cancer to the Metabolism Drug Phenformin

被引：466

作者：

Shackelford, David B. ^{[1
,4
]}

Abt, Evan ^{[4
]}

Gerken, Laurie ^{[1
]}

Vasquez, Debbie S. ^{[1
]}

Seki, Atsuko ^{[3
]}

Leblanc, Mathias ^{[1
]}

Wei, Liu ^{[4
]}

Fishbein, Michael C. ^{[3
]}

Czernin, Johannes ^{[4
]}

Mischel, Paul S. ^{[3
,4
]}

Shaw, Reuben J. ^{[1
,2
]}

机构：

[1] Salk Inst Biol Studies, Dulbecco Ctr Canc Res, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[2] Salk Inst Biol Studies, Howard Hughes Med Inst, Dulbecco Ctr Canc Res, La Jolla, CA 92037 USA

[3] David Geffen UCLA Sch Med, Dept Pathol & Lab Med, Los Angeles, CA 90095 USA

[4] David Geffen UCLA Sch Med, Los Angeles, CA 90095 USA

来源：

CANCER CELL | 2013年 / 23卷 / 02期

基金：

美国国家卫生研究院;

关键词：

LKB1-AMPK PATHWAY; RESPIRATORY-CHAIN; AMPK ACTIVATION; ENERGY STRESS; COMPLEX I; METFORMIN; SURVIVAL; KINASE; PHOSPHORYLATION; HOMEOSTASIS;

D O I：

10.1016/j.ccr.2012.12.008

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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.

引用

页码：143 / 158

页数：16

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