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mTOR target NDRG1 confers MGMT-dependent resistance to alkylating chemotherapy

Markus Weiler1, Jonas Blaes, Stefan Pusch

  • 1German 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.

Proceedings of the National Academy of Sciences of the United States of America
|December 25, 2013
PubMed

Insights

Hypoxia and certain therapies increase resistance to alkylating chemotherapy by activating NDRG1. This protein stabilizes MGMT, a key enzyme for chemoresistance, impacting patient outcomes in malignant gliomas.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Hypoxic microenvironments and therapies like irradiation and corticosteroids can induce chemoresistance.
  • The mammalian target of rapamycin (mTOR) pathway is implicated in hypoxia-induced chemoresistance, but mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms of mTOR-mediated hypoxia-induced chemoresistance.
  • To identify key molecular determinants of resistance to alkylating chemotherapy.

Main Methods:

  • Investigated the role of N-myc downstream regulated gene 1 (NDRG1) in chemoresistance.
  • Analyzed molecular pathways involving hypoxia-inducible factor (HIF)-1alpha, p53, and mTOR complex 2 (mTORC2)/serum glucocorticoid-induced protein kinase 1 (SGK1).
  • Examined NDRG1 expression and activity in posttreatment tumor tissues from patients with malignant gliomas and glioblastoma.

Main Results:

  • NDRG1 was identified as a key determinant of resistance to alkylating chemotherapy, induced by hypoxia and other therapies.
  • Resistance to alkylating chemotherapy, but not radiotherapy, was dependent on NDRG1.
  • NDRG1 stabilizes methyltransferases, including O(6)-methylguanine-DNA methyltransferase (MGMT), a critical enzyme for alkylating agent resistance.
  • In glioblastoma patients, NDRG1 was induced in posttreatment tumor tissue and predicted poor response to alkylating chemotherapy.
  • MGMT promoter methylation lost predictive value for alkylating chemotherapy response in patients receiving corticosteroids.

Conclusions:

  • NDRG1 is a crucial mediator of alkylating chemotherapy resistance, driven by various factors including hypoxia and therapeutic interventions.
  • NDRG1's stabilization of MGMT is a key molecular mechanism underlying chemoresistance in malignant gliomas.
  • Clinical data suggests NDRG1 as a predictive biomarker for poor response to alkylating chemotherapy, particularly in the context of corticosteroid use.

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