Helen J Hülsmann1, Jana Rolff2, Christian Bender3, Mostafa Jarahian4, Ulrike Korf3, Ralf Herwig5, Holger Fröhlich6, Michael Thomas7, Johannes Merk8, Iduna Fichtner9, Holger Sültmann10, Ruprecht Kuner11. 1. Unit Cancer Genome Research, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany. 2. Experimental Pharmacology, Max-Delbrück-Center, Berlin, Germany; Experimental Pharmacology & Oncology Berlin-Buch GmbH, Berlin, Germany. 3. Division of Molecular Genome Analysis, German Cancer Research Center, Heidelberg, Germany. 4. Translational Immunology Unit, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany. 5. Vertebrate Genomics Department, Max Planck Institute for Molecular Genetics, Berlin, Germany. 6. University of Bonn, Bonn-Aachen International Center for IT, Bonn, Germany. 7. 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. 8. Evangelische Lungenklinik, Berlin, Germany. 9. Experimental Pharmacology, Max-Delbrück-Center, Berlin, Germany. 10. 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. 11. 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.
Abstract
OBJECTIVES: 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. MATERIALS AND 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. CONCLUSION: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models.
OBJECTIVES: 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 adenocarcinomapatients 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. MATERIALS AND METHODS:Erlotinib-response associated proteins were investigated in patient-derived NSCLCmouse 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. CONCLUSION: Our results suggest that AMPK activation status affects response to erlotinib in distinct lung tumor models.
Authors: Mohamad K Hammoud; Hesham K Yosef; Tatjana Lechtonen; Karim Aljakouch; Martin Schuler; Wissam Alsaidi; Ibrahim Daho; Abdelouahid Maghnouj; Stephan Hahn; Samir F El-Mashtoly; Klaus Gerwert Journal: Sci Rep Date: 2018-10-15 Impact factor: 4.379
Authors: Christian Faltus; Angelika Lahnsteiner; Myrto Barrdahl; Yassen Assenov; Anika Hüsing; Olga Bogatyrova; Marina Laplana; Theron Johnson; Thomas Muley; Michael Meister; Arne Warth; Michael Thomas; Christoph Plass; Rudolf Kaaks; Angela Risch Journal: Int J Mol Sci Date: 2022-09-14 Impact factor: 6.208