title: mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy.
abstract: 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.
authors.affiliation: German Cancer Consortium, Clinical Cooperation Units Neurooncology and Neuropathology, Helmholtz Group Experimental Neuroimmunology, Small Animal Imaging Facility, Biostatistics, and Functional Proteome Analysis, German Cancer Research Center, D-69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Weiler
authors.forename: Jonas
authors.initials: J
authors.lastname: Blaes
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.forename: Felix
authors.initials: F
authors.lastname: Sahm
authors.forename: Marcus
authors.initials: M
authors.lastname: Czabanka
authors.forename: Sebastian
authors.initials: S
authors.lastname: Luger
authors.forename: Lukas
authors.initials: L
authors.lastname: Bunse
authors.forename: Gergely
authors.initials: G
authors.lastname: Solecki
authors.forename: Viktoria
authors.initials: V
authors.lastname: Eichwald
authors.forename: Manfred
authors.initials: M
authors.lastname: Jugold
authors.forename: Sibylle
authors.initials: S
authors.lastname: Hodecker
authors.forename: Matthias
authors.initials: M
authors.lastname: Osswald
authors.forename: Christoph
authors.initials: C
authors.lastname: Meisner
authors.forename: Thomas
authors.initials: T
authors.lastname: Hielscher
authors.forename: Petra
authors.initials: P
authors.lastname: Rübmann
authors.forename: Philipp-Niklas
authors.initials: PN
authors.lastname: Pfenning
authors.forename: Michael
authors.initials: M
authors.lastname: Ronellenfitsch
authors.forename: Tore
authors.initials: T
authors.lastname: Kempf
authors.forename: Martina
authors.initials: M
authors.lastname: Schnölzer
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Martin
authors.initials: M
authors.lastname: Bendszus
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Frank
authors.initials: F
authors.lastname: Winkler
authors.forename: Michael
authors.initials: M
authors.lastname: Weller
authors.forename: Peter
authors.initials: P
authors.lastname: Vajkoczy
authors.forename: Michael
authors.initials: M
authors.lastname: Platten
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wick
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000378:metabolism*; D004260:DNA Repair; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D005910:Glioma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000860:Hypoxia; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D016086:Lentivirus / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000494:pharmacology*; D010957:Plasmids / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D013997:Time Factors; D000099259:N-myc Downstream-Regulated Gene 1 Protein
chemical_list: D018906:Antineoplastic Agents, Alkylating; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D019853:O(6)-Methylguanine-DNA Methyltransferase; D058570:TOR Serine-Threonine Kinases; D000099259:N-myc Downstream-Regulated Gene 1 Protein; C546842:MTOR protein, human