mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

作者：Weiler Markus; Blaes Jonas; Pusch Stefan; Sahm Felix; Czabanka Marcus; Luger Sebastian; Bunse Lukas; Solecki Gergely; Eichwald Viktoria; Jugold Manfred; Hodecker Sibylle; Osswald Matthias; Meisner Christoph; Hielscher Thomas; Ruebmann Petra; Pfenning Philipp Niklas; Ronellenfitsch Michael; Kempf Tore; Schnoelzer Martina; Abdollahi Amir; Lang Florian; Bendszus Martin; von Deimling Andreas; Winkler Frank; Weller Michael; Vajkoczy Peter; Platten Michael; Wick Wolfgang^*

来源：Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(1): 409-414.

DOI：10.1073/pnas.1314469111

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.

• 出版日期2014-1-7