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Published on: December 15, 2010
Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment
Dennis Heinzen1, Iris Divé2,3,4, Nadja I Lorenz5,6,7
1Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Dennis.heinzen@gmx.de.
Abstract:
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.
Insights
New mTOR inhibitors show promise against glioblastoma by blocking cell growth. However, these drugs may unexpectedly protect tumor cells in low-oxygen, nutrient-poor environments, requiring cautious application.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metabolism
Background:
- Glioblastomas (GBs) often show activated epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (mTOR) pathways.
- mTOR functions in two complexes: mTORC1 and mTORC2. mTORC1 inhibitors like rapamycin have shown limited success in GB clinical trials.
- Next-generation ATP-competitive inhibitors targeting both mTOR complexes are available, but their impact on GB metabolism is not well understood.
Purpose of the Study:
- To compare the efficacy of ATP-competitive mTORC1/2 inhibitors (torin2, INK-128, NVP-Bez235) against the allosteric mTORC1 inhibitor rapamycin.
- To investigate the effects of these inhibitors on glioblastoma cell metabolism under conditions mimicking the tumor microenvironment (hypoxia, nutrient deprivation).
Main Methods:
- Treatment of glioblastoma cells with various mTOR inhibitors (torin2, INK-128, NVP-Bez235, rapamycin).
- Assessment of mTORC1 and mTORC2 signaling inhibition.
- Evaluation of cell growth, cell cycle arrest, and metabolic changes (oxygen and glucose consumption) under normoxic and hypoxic/nutrient-poor conditions.
Main Results:
- ATP-competitive mTORC1/2 inhibitors (INK-128, NVP-Bez235) more effectively inhibited mTORC1 signaling and cell growth than rapamycin, partly via cell cycle arrest.
- Under hypoxic and nutrient-poor conditions, mTORC1/2 inhibitors demonstrated stronger cytoprotective effects than rapamycin.
- These protective effects were mediated by reduced oxygen and glucose consumption by tumor cells.
Conclusions:
- While potent mTORC1/2 inhibitors can arrest glioblastoma cell proliferation, they may also enhance tumor cell survival in challenging microenvironments.
- Therapies targeting proliferation and metabolism need careful consideration in hypoxic glioblastomas.
- Caution is advised when using mTOR inhibitors in glioblastomas with physiological or therapeutic hypoxia.
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