title: LKB1 deficiency enhances sensitivity to energetic stress induced by erlotinib treatment in non-small-cell lung cancer (NSCLC) cells.
abstract: The tumor suppressor serine/threonine kinase 11 (STK11 or LKB1) is mutated in 20-30% of patients with non-small-cell lung cancer (NSCLC). Loss of LKB1-adenosine monophosphate-activated protein kinase (AMPK) signaling confers sensitivity to metabolic inhibition or stress-induced mitochondrial insults. We tested the hypothesis that loss of LKB1 sensitizes NSCLC cells to energetic stress induced by treatment with erlotinib. LKB1-deficient cells exhibited enhanced sensitivity to erlotinib in vitro and in vivo that was associated with alterations in energy metabolism and mitochondrial dysfunction. Loss of LKB1 expression altered the cellular response to erlotinib treatment, resulting in impaired ATP homeostasis and an increase in reactive oxygen species. Furthermore, erlotinib selectively blocked mammalian target of rapamycin signaling, inhibited cell growth and activated apoptosis in LKB1-deficient cells. Erlotinib treatment also induced AMPK activation despite loss of LKB1 expression, which was partially reduced by the application of a calcium/calmodulin-dependent protein kinase kinase 2 inhibitor (STO-609) or calcium chelator (BAPTA-AM). These findings may have significant implications for the design of novel NSCLC treatments that target dysregulated metabolic and signaling pathways in LKB1-deficient tumors.
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: Y M
authors.initials: YM
authors.lastname: Whang
authors.affiliation: Center for Bone Biology, Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: S I
authors.initials: SI
authors.lastname: Park
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: I A
authors.initials: IA
authors.lastname: Trenary
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.
authors.forename: R A
authors.initials: RA
authors.lastname: Egnatchik
authors.affiliation: Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University, Nashville, TN, USA.
authors.forename: J P
authors.initials: JP
authors.lastname: Fessel
authors.affiliation: Department of Cancer Biology, Vanderbilt University, Nashville, TN, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Kaufman
authors.affiliation: Department of Internal Medicine, The Ohio State University Medical Center, Columbus, OH, USA.
authors.forename: D P
authors.initials: DP
authors.lastname: Carbone
authors.affiliation: Department of Chemical and Biomolecular Engineering, Vanderbilt University, Nashville, TN, USA.|Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
authors.forename: J D
authors.initials: JD
authors.lastname: Young
mesh_terms: D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004734:Energy Metabolism / Q000187:drug effects; D000069347:Erlotinib Hydrochloride / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D055785:Gene Knockdown Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D034741:RNA, Small Interfering; D000069347:Erlotinib Hydrochloride; D017346:Protein Serine-Threonine Kinases; C109790:STK11 protein, human; D000091162:AMP-Activated Protein Kinase Kinases