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

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

Nature communications (2020-09-19)
Niklas Gremke, Pierfrancesco Polo, Aaron Dort, Jean Schneikert, Sabrina Elmshäuser, Corinna Brehm, Ursula Klingmüller, Anna Schmitt, Hans Christian Reinhardt, Oleg Timofeev, Michael Wanzel, Thorsten Stiewe
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Monoclonal ANTI-FLAG® M2 antibody produced in mouse, 1 mg/mL, clone M2, affinity isolated antibody, buffered aqueous solution (50% glycerol, 10 mM sodium phosphate, and 150 mM NaCl, pH 7.4)
Sigma-Aldrich
3-Methyladenine, autophagy inhibitor
Sigma-Aldrich
Crystal violet solution
Sigma-Aldrich
Anti-p62/SQSTM1 antibody produced in rabbit, ~1 mg/mL, affinity isolated antibody, buffered aqueous solution