PMID- 31510109 OWN - NLM STAT- MEDLINE DCOM- 20200210 LR - 20220727 IS - 1422-0067 (Electronic) IS - 1422-0067 (Linking) VI - 20 IP - 18 DP - 2019 Sep 10 TI - Second Generation mTOR Inhibitors as a Double-Edged Sword in Malignant Glioma Treatment. LID - 10.3390/ijms20184474 [doi] LID - 4474 AB - 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. FAU - Heinzen, Dennis AU - Heinzen D AD - Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. Dennis.heinzen@gmx.de. FAU - Dive, Iris AU - Dive I AD - Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. iris.dive@kgu.de. AD - University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. iris.dive@kgu.de. AD - German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. iris.dive@kgu.de. FAU - Lorenz, Nadja I AU - Lorenz NI AD - Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. nadja.lorenz@googlemail.com. AD - University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. nadja.lorenz@googlemail.com. AD - German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. nadja.lorenz@googlemail.com. FAU - Luger, Anna-Luisa AU - Luger AL AD - Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. anna-luisa.luger@kgu.de. AD - University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. anna-luisa.luger@kgu.de. AD - German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. anna-luisa.luger@kgu.de. FAU - Steinbach, Joachim P AU - Steinbach JP AD - Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. joachim.steinbach@med.uni-frankfurt.de. AD - University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. joachim.steinbach@med.uni-frankfurt.de. AD - German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. joachim.steinbach@med.uni-frankfurt.de. AD - Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany. joachim.steinbach@med.uni-frankfurt.de. FAU - Ronellenfitsch, Michael W AU - Ronellenfitsch MW AUID- ORCID: 0000-0002-1402-6290 AD - Dr. Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Schleusenweg 2-16, 60528 Frankfurt am Main, Germany. m.ronellenfitsch@gmx.net. AD - University Cancer Center Frankfurt (UCT), University Hospital Frankfurt, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. m.ronellenfitsch@gmx.net. AD - German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, Theodor-Stern-Kai 7, 60590 Frankfurt am Main, Germany. m.ronellenfitsch@gmx.net. AD - Frankfurt Cancer Institute (FCI), University Hospital Frankfurt, Paul-Ehrlich-Strasse 42-44, 60596 Frankfurt am Main, Germany. m.ronellenfitsch@gmx.net. LA - eng GR - -/Senckenberg Foundation/ GR - -/Frankfurter Forschungsforderung/ GR - -/Frankfurt research funding/ GR - -/UCT Frankfurt/ GR - -/Else-Kroner-Kolleg Frankfurt/ PT - Journal Article DEP - 20190910 PL - Switzerland TA - Int J Mol Sci JT - International journal of molecular sciences JID - 101092791 RN - 0 (9-(6-aminopyridin-3-yl)-1-(3-(trifluoromethyl)phenyl)benzo(h)(1,6)naphthyridin-2(1H)-one) RN - 0 (Benzoxazoles) RN - 0 (Imidazoles) RN - 0 (Naphthyridines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Pyrimidines) RN - 0 (Quinolines) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1) RN - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 2) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - JGH0DF1U03 (sapanisertib) RN - RUJ6Z9Y0DT (dactolisib) RN - W36ZG6FT64 (Sirolimus) SB - IM MH - Apoptosis/*drug effects MH - Benzoxazoles/pharmacology MH - Cell Cycle Checkpoints/drug effects MH - Cell Line, Tumor MH - Cell Proliferation/*drug effects MH - Glioma/drug therapy/*metabolism/pathology MH - Humans MH - Imidazoles/pharmacology MH - Mechanistic Target of Rapamycin Complex 1/antagonists & inhibitors/metabolism MH - Mechanistic Target of Rapamycin Complex 2/antagonists & inhibitors/metabolism MH - Naphthyridines/pharmacology MH - Protein Kinase Inhibitors/*pharmacology MH - Pyrimidines/pharmacology MH - Quinolines/pharmacology MH - Signal Transduction/*drug effects MH - Sirolimus/pharmacology MH - TOR Serine-Threonine Kinases/*antagonists & inhibitors/metabolism PMC - PMC6770420 OTO - NOTNLM OT - glioblastoma OT - hypoxia OT - mTOR OT - mTOR inhibition OT - starvation OT - tumor microenvironment COIS- The authors declare no conflict of interest. EDAT- 2019/09/13 06:00 MHDA- 2020/02/11 06:00 PMCR- 2019/09/01 CRDT- 2019/09/13 06:00 PHST- 2019/05/16 00:00 [received] PHST- 2019/08/21 00:00 [revised] PHST- 2019/09/08 00:00 [accepted] PHST- 2019/09/13 06:00 [entrez] PHST- 2019/09/13 06:00 [pubmed] PHST- 2020/02/11 06:00 [medline] PHST- 2019/09/01 00:00 [pmc-release] AID - ijms20184474 [pii] AID - ijms-20-04474 [pii] AID - 10.3390/ijms20184474 [doi] PST - epublish SO - Int J Mol Sci. 2019 Sep 10;20(18):4474. doi: 10.3390/ijms20184474.