BIOLOGICAL SCIENCES: Medical Sciences The mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

A hypoxic microenvironment induces resistance to alkylating agents by activating targets in the mammalian target of rapamycin (mTOR) pathway. The molecular mechanisms involved in this mTOR-mediated hypoxia-induced chemoresistance, however, are unclear. Here we identify the mTOR target N-myc downstream regulated gene 1 (NDRG1) as a key determinant of resistance toward alkylating chemotherapy, driven by hypoxia but also by therapeutic measures such as irradiation, corticosteroids, and chronic exposure to alkylating agents via distinct molecular routes involving hypoxia-inducible factor (HIF)-1alpha, p53, and the mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1) pathway. Resistance toward alkylating chemotherapy but not radiotherapy was dependent on NDRG1 expression and activity. In posttreatment tumor tissue of patients with malignant gliomas, NDRG1 was induced and predictive of poor response to alkylating chemotherapy. On a molecular level, NDRG1 bound and stabilized methyltransferases, chiefly O(6)-methylguanine-DNA methyltransferase (MGMT), a key enzyme for resistance to alkylating agents in glioblastoma patients. In patients with glioblastoma, MGMT promoter methylation in tumor tissue was not more predictive for response to alkylating chemotherapy in patients who received concomitant corticosteroids. DOI: https://doi.org/10.1073/pnas.1314469111 Posted at the Zurich Open Repository and Archive, University of Zurich ZORA URL: https://doi.org/10.5167/uzh-95401 Originally published at: Weiler, M; Blaes, J; Pusch, S; Sahm, F; Czabanka, M; Luger, S; Bunse, L; Solecki, G; Eichwald, V; Jugold, M; Hodecker, S; Osswald, M; Meisner, C; Hielscher, T; Rübmann, P; Pfenning, P N; Ronellenfitsch, M; Kempf, T; Schnölzer, M; Abdollahi, A; Lang, F; Bendszus, M; von Deimling, A; Winkler, F; Weller, M; Vajkoczy, P; Platten, M; Wick, W (2014). mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy. Proceedings of the National Academy of Sciences of the United States of America, 111(1):409-414. DOI: https://doi.org/10.1073/pnas.1314469111 BIOLOGICAL SCIENCES: Medical Sciences The mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy Markus Weiler, Jonas Blaes, Stefan Pusch, Felix Sahm, Marcus Czabanka, Sebastian Luger, Lukas Bunse, Gergely Solecki, Viktoria Eichwald, Manfred Jugold, Sibylle C. Hodecker, Matthias Osswald, Christoph Meisner, Thomas Hielscher, Petra Rübmann, Philipp-Niclas Pfenning, Michael Ronellenfitsch, Tore Kempf, Martina Schnölzer, Amir Abdollahi, Florian Lang, Martin Bendszus, Andreas von Deimling, Frank Winkler, Michael Weller, Peter Vajkoczy, Michael Platten and Wolfgang Wick German Cancer Consortium (DKTK), Clinical Cooperation Units Neurooncology and Neuropathology, Functional Proteome Analysis, Helmholtz Group Experimental Neuroimmunology Biostatistics, and Small Animal Imaging Facility, German Cancer Research Center (DKFZ), INF 280, D-69120 Heidelberg; Departments of Neurooncology and Radiation Oncology at the National Center for Tumor Diseases, Departments of Neuroradiology and Neuropathology, University Hospital Heidelberg, INF 400, D-69120 Heidelberg; Neurosurgery Clinic Charité, University Medicine Berlin, Augustenburger Platz 1, D-13353 Berlin; Department of Medical Biometry and Physiology, Geissweg 3, D-72076 Tübingen, University of Tübingen; Dr. Senckenberg Institute of Neurooncology, Goethe-University Hospital Frankfurt, Schleusenweg 2-16, 
 D-60528 Frankfurt am Main; all Germany; Department of Neurology, Frauenklinikstrasse 26, CH-8090 Zurich, University Hospital Zurich, Switzerland These authors contributed equally to this work Correspondence: Wolfgang Wick, MD, Department of Neurooncology, Neurology Clinic and National Center for Tumor Diseases, University Hospital Heidelberg, Im Neuenheimer Feld 400, D-69120