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Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment

Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in c...

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Autores principales: Heinzen, Dennis, Divé, Iris, Lorenz, Nadja I., Luger, Anna-Luisa, Steinbach, Joachim P., Ronellenfitsch, Michael W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770420/
https://www.ncbi.nlm.nih.gov/pubmed/31510109
http://dx.doi.org/10.3390/ijms20184474
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author Heinzen, Dennis
Divé, Iris
Lorenz, Nadja I.
Luger, Anna-Luisa
Steinbach, Joachim P.
Ronellenfitsch, Michael W.
author_facet Heinzen, Dennis
Divé, Iris
Lorenz, Nadja I.
Luger, Anna-Luisa
Steinbach, Joachim P.
Ronellenfitsch, Michael W.
author_sort Heinzen, Dennis
collection PubMed
description Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors.
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spelling pubmed-67704202019-10-30 Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment Heinzen, Dennis Divé, Iris Lorenz, Nadja I. Luger, Anna-Luisa Steinbach, Joachim P. Ronellenfitsch, Michael W. Int J Mol Sci Article Glioblastomas (GBs) frequently display activation of the epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR). mTOR exists as part of two multiprotein complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). In GBs, mTORC1 inhibitors such as rapamycin have performed poorly in clinical trials, and in vitro protect GB cells from nutrient and oxygen deprivation. Next generation ATP-competitive mTOR inhibitors with affinity for both mTOR complexes have been developed, but data exploring their effects on GB metabolism are scarce. In this study, we compared the ATP-competitive mTORC1/2 inhibitors torin2, INK-128 and NVP-Bez235 to the allosteric mTORC1 inhibitor rapamycin under conditions that mimic the glioma microenvironment. In addition to inhibiting mTORC2 signaling, INK-128 and NVP-Bez235 more effectively blocked mTORC1 signaling and prompted a stronger cell growth inhibition, partly by inducing cell cycle arrest. However, under hypoxic and nutrient-poor conditions mTORC1/2 inhibitors displayed even stronger cytoprotective effects than rapamycin by reducing oxygen and glucose consumption. Thus, therapies that arrest proliferation and inhibit anabolic metabolism must be expected to improve energy homeostasis of tumor cells. These results mandate caution when treating physiologically or therapeutically induced hypoxic GBs with mTOR inhibitors. MDPI 2019-09-10 /pmc/articles/PMC6770420/ /pubmed/31510109 http://dx.doi.org/10.3390/ijms20184474 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Heinzen, Dennis
Divé, Iris
Lorenz, Nadja I.
Luger, Anna-Luisa
Steinbach, Joachim P.
Ronellenfitsch, Michael W.
Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
title Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
title_full Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
title_fullStr Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
title_full_unstemmed Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
title_short Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
title_sort second generation mtor inhibitors as a double-edged sword in malignant glioma treatment
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6770420/
https://www.ncbi.nlm.nih.gov/pubmed/31510109
http://dx.doi.org/10.3390/ijms20184474
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