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Your search keyword '"Elmshäuser, Sabrina"' showing total 2 results
Start Over Author "Elmshäuser, Sabrina" Publisher nature publishing group
2 results on '"Elmshäuser, Sabrina"'

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

Author

Gremke, Niklas, Polo, Pierfrancesco, Dort, Aaron, Schneikert, Jean, Elmshäuser, Sabrina, Brehm, Corinna, Klingmüller, Ursula, Schmitt, Anna, Reinhardt, Hans Christian, Timofeev, Oleg, Wanzel, Michael, and Stiewe, Thorsten

Subjects
Male, Lung Neoplasms, Cell Survival, Science, Medizin, Antineoplastic Agents, Apoptosis, Deoxyglucose, Mechanistic Target of Rapamycin Complex 1, Article, Mice, Drug Therapy, Cell Line, Tumor, Autophagy, Animals, Humans, lcsh:Science, TOR Serine-Threonine Kinases, Cancer metabolism, Xenograft Model Antitumor Assays, Cancer therapeutic resistance, Drug Resistance, Neoplasm, TOR signalling, Female, lcsh:Q, biological phenomena, cell phenomena, and immunity, Signal Transduction
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., mTORC1 is a key mediator of drug resistance and also regulates autophagy. In this study, the authors demonstrate that cancer cells with acquired drug resistance exibit metabolic vulnerabilities mediated by high levels of mTORC1 and the consequent inhibition of autophagy.

Published
2020

2. p53 partial loss-of-function mutations sensitize to chemotherapy.

Author

Klimovich B, Merle N, Neumann M, Elmshäuser S, Nist A, Mernberger M, Kazdal D, Stenzinger A, Timofeev O, and Stiewe T

Subjects
Animals, Humans, Mice, Drug Resistance, Neoplasm genetics, Apoptosis genetics, Apoptosis drug effects, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal drug therapy, Carcinoma, Pancreatic Ductal pathology, Lung Neoplasms genetics, Lung Neoplasms drug therapy, Lung Neoplasms pathology, Cell Line, Tumor, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute drug therapy, Leukemia, Myeloid, Acute pathology, Pancreatic Neoplasms genetics, Pancreatic Neoplasms drug therapy, Pancreatic Neoplasms pathology, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Loss of Function Mutation
Abstract

The tumor suppressive transcription factor p53 is frequently inactivated in cancer cells by missense mutations that cluster in the DNA binding domain. 30% hit mutational hotspot residues, resulting in a complete loss of transcriptional activity and mutant p53-driven chemotherapy resistance. Of the remaining 70% of non-hotspot mutants, many are partial loss-of-function (partial-LOF) mutants with residual transcriptional activity. The therapeutic consequences of a partial-LOF have remained largely elusive. Using a p53 mutation engineered to reduce DNA binding, we demonstrate that partial-LOF is sufficient to enhance oncogene-driven tumorigenesis in mouse models of lung and pancreatic ductal adenocarcinoma and acute myeloid leukemia. Interestingly, mouse and human tumors with partial-LOF mutations showed mutant p53 protein accumulation similar as known for hotspot mutants. Different from the chemotherapy resistance caused by p53-loss, the partial-LOF mutant sensitized to an apoptotic chemotherapy response and led to a survival benefit. Mechanistically, the pro-apoptotic transcriptional activity of mouse and human partial-LOF mutants was rescued at high mutant protein levels, suggesting that accumulation of partial-LOF mutants enables the observed apoptotic chemotherapy response. p53 non-hotspot mutants with partial-LOF, therefore, represent tumorigenic p53 mutations that need to be distinguished from other mutations because of their beneficial impact on survival in a therapy context., (© 2021. The Author(s).)

Published
2022
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