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

详细信息    查看全文

• 作者：David B. Shackelford¹ ; ⁴ ; ⁵ ; ^{dshackelford@mednet.ucla.edu} ; Evan Abt⁴ ; ⁵ ; Laurie Gerken¹ ; Debbie S. Vasquez¹ ; Atsuko Seki³ ; Mathias Leblanc¹ ; Liu Wei⁴ ; Michael C. Fishbein³ ; Johannes Czernin⁴ ; Paul S. Mischel³ ; ⁴ ; ⁶ ; Reuben J. Shaw¹ ; ² ; ^{shaw@salk.edu}
• 刊名：Cancer Cell
• 出版年：2013
• 出版时间：11 February, 2013
• 年：2013
• 卷：23
• 期：2
• 页码：143-158
• 全文大小：3191 K

文摘

| Figures/TablesFigures/Tables | ReferencesReferences

Summary

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.