mTOR-mediated cancer drug resistance suppresses autophagy and generates a druggable metabolic vulnerability.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
/ drug effects
Autophagy
/ genetics
Cell Line, Tumor
Cell Survival
/ drug effects
Deoxyglucose
Drug Resistance, Neoplasm
/ drug effects
Drug Therapy
Female
Humans
Lung Neoplasms
Male
Mechanistic Target of Rapamycin Complex 1
Mice
Signal Transduction
/ drug effects
TOR Serine-Threonine Kinases
/ metabolism
Xenograft Model Antitumor Assays
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
17 09 2020
17 09 2020
Historique:
received:
26
03
2020
accepted:
25
08
2020
entrez:
18
9
2020
pubmed:
19
9
2020
medline:
6
10
2020
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 32943635
doi: 10.1038/s41467-020-18504-7
pii: 10.1038/s41467-020-18504-7
pmc: PMC7499183
doi:
Substances chimiques
Antineoplastic Agents
0
Deoxyglucose
9G2MP84A8W
MTOR protein, human
EC 2.7.1.1
Mechanistic Target of Rapamycin Complex 1
EC 2.7.11.1
TOR Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
4684Références
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