mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability

Niklas Gremke, Pierfrancesco Polo, Aaron Dort, Jean Schneikert, Sabrina Elmshäuser, Corinna Brehm, Ursula Klingmüller, Anna Schmitt, Hans Christian Reinhardt, Oleg Timofeev, Michael Wanzel and Thorsten Stiewe ()
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Niklas Gremke: Institute of Molecular Oncology, Philipps-University
Pierfrancesco Polo: Institute of Molecular Oncology, Philipps-University
Aaron Dort: Institute of Molecular Oncology, Philipps-University
Jean Schneikert: Institute of Molecular Oncology, Philipps-University
Sabrina Elmshäuser: Institute of Molecular Oncology, Philipps-University
Corinna Brehm: Institute of Pathology, Philipps-University
Ursula Klingmüller: German Cancer Research Center (DKFZ)
Anna Schmitt: University Hospital Essen, German Cancer Consortium (DKTK)
Hans Christian Reinhardt: University Hospital Essen, German Cancer Consortium (DKTK)
Oleg Timofeev: Institute of Molecular Oncology, Philipps-University
Michael Wanzel: Institute of Molecular Oncology, Philipps-University
Thorsten Stiewe: Institute of Molecular Oncology, Philipps-University

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Cancer cells have a characteristic metabolism, mostly caused by alterations in signal transduction networks rather than mutations in metabolic enzymes. For metabolic drugs to be cancer-selective, signaling alterations need to be identified that confer a druggable vulnerability. Here, we demonstrate that many tumor cells with an acquired cancer drug resistance exhibit increased sensitivity to mechanistically distinct inhibitors of cancer metabolism. We demonstrate that this metabolic vulnerability is driven by mTORC1, which promotes resistance to chemotherapy and targeted cancer drugs, but simultaneously suppresses autophagy. We show that autophagy is essential for tumor cells to cope with therapeutic perturbation of metabolism and that mTORC1-mediated suppression of autophagy is required and sufficient for generating a metabolic vulnerability leading to energy crisis and apoptosis. Our study links mTOR-induced cancer drug resistance to autophagy defects as a cause of a metabolic liability and opens a therapeutic window for the treatment of otherwise therapy-refractory tumor patients.

Date: 2020
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DOI: 10.1038/s41467-020-18504-7

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