title: Activation of AMP-activated protein kinase sensitizes lung cancer cells and H1299 xenografts to erlotinib.
abstract: OBJECTIVE
  The therapeutic scheme for non-small cell lung cancer (NSCLC) patients can be improved if adapted to the individual response. For example, 60-70% of adenocarcinoma patients show response to EGFR-tyrosine kinase inhibitors in the presence of mutated EGFR. We searched for additional target molecules involved in the action of the EGFR-tyrosine kinase inhibitor erlotinib in the absence of EGFR mutations, which might be suitable for combinatorial therapy approaches.
  
  
  METHODS
  Erlotinib-response associated proteins were investigated in patient-derived NSCLC mouse xenografts by reverse-phase protein array technology (RPPA) and Western blotting. A combinatorial treatment approach was carried out in NSCLC cell lines and H1299 mouse xenografts, and subsequently analyzed for consequences in cell growth and signal transduction.
  
  
  RESULTS
  AMP-activated protein kinase (AMPK) expression was increased in erlotinib responders before and after treatment. In a combinatorial approach, activation of AMPK by A-769662 and erlotinib treatment showed a synergistic effect in cell growth reduction and apoptosis activation in H1299 cells compared to the single drugs. AMPK pathway analyses revealed an effective inhibition of mTOR signaling by drug combination. In H1299 xenografts, the tumor size was significantly decreased after combinatorial treatment.
  
  
  CONCLUSIONS
  Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models.
authors.affiliation: Unit Cancer Genome Research, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Helen J
authors.initials: HJ
authors.lastname: Hülsmann
authors.affiliation: Experimental Pharmacology, Max-Delbrück-Center, Berlin, Germany; Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany.
authors.forename: Jana
authors.initials: J
authors.lastname: Rolff
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Bender
authors.affiliation: Translational Immunology Unit, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany.
authors.forename: Mostafa
authors.initials: M
authors.lastname: Jarahian
authors.affiliation: Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Korf
authors.affiliation: Vertebrate Genomics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Herwig
authors.affiliation: University of Bonn, Bonn-Aachen International Center for IT, Bonn, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Fröhlich
authors.affiliation: Internistische Onkologie der Thoraxtumoren, Thoraxklinik im Universitätsklinikum, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Thomas
authors.affiliation: Evangelische Lungenklinik, Berlin, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Merk
authors.affiliation: Experimental Pharmacology, Max-Delbrück-Center, Berlin, Germany.
authors.forename: Iduna
authors.initials: I
authors.lastname: Fichtner
authors.affiliation: Unit Cancer Genome Research, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg, Germany. Electronic address: h.sueltmann@dkfz.de.
authors.forename: Holger
authors.initials: H
authors.lastname: Sültmann
authors.affiliation: Unit Cancer Genome Research, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research, Heidelberg, Germany.
authors.forename: Ruprecht
authors.initials: R
authors.lastname: Kuner
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001713:Biphenyl Compounds; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D004789:Enzyme Activation / Q000187:drug effects; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011753:Pyrones / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013876:Thiophenes / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D001713:Biphenyl Compounds; D047428:Protein Kinase Inhibitors; D011753:Pyrones; D011799:Quinazolines; D013876:Thiophenes; D000069347:Erlotinib Hydrochloride; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C512408:4-hydroxy-3-(4-(2-hydroxyphenyl)phenyl)-6-oxo-7H-thieno(2,3-b)pyridine-5-carbonitrile
keywords: AMPK; EGFR; Erlotinib; Lung cancer; Xenograft models