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

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.

• Authors: Dennis Heinzen, Iris Divé, Nadja I Lorenz, Anna-Luisa Luger, Joachim P Steinbach, Michael W Ronellenfitsch
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 20 Issue 18 (Sep 10 2019) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 31510109 (Publication Type: Journal Article)

Chemical References

• 9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one
• Benzoxazoles
• Imidazoles
• Naphthyridines
• Protein Kinase Inhibitors
• Pyrimidines
• Quinolines
• Mechanistic Target of Rapamycin Complex 1
• Mechanistic Target of Rapamycin Complex 2
• TOR Serine-Threonine Kinases
• sapanisertib
• dactolisib
• Sirolimus

Topics

• Apoptosis (drug effects)
• Benzoxazoles (pharmacology)
• Cell Cycle Checkpoints (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Glioma (drug therapy, metabolism, pathology)
• Humans
• Imidazoles (pharmacology)
• Mechanistic Target of Rapamycin Complex 1 (antagonists & inhibitors, metabolism)
• Mechanistic Target of Rapamycin Complex 2 (antagonists & inhibitors, metabolism)
• Naphthyridines (pharmacology)
• Protein Kinase Inhibitors (pharmacology)
• Pyrimidines (pharmacology)
• Quinolines (pharmacology)
• Signal Transduction (drug effects)
• Sirolimus (pharmacology)
• TOR Serine-Threonine Kinases (antagonists & inhibitors, metabolism)